System for Controlling the Reactivity of Boronic Acids

ABSTRACT

A protected organoboronic acid includes a boron having an sp 3  hybridization, a conformationally rigid protecting group bonded to the boron, and an organic group bonded to the boron through a boron-carbon bond. A method of performing a chemical reaction includes contacting a protected organoboronic acid with a reagent, the protected organoboronic acid including a boron having an sp 3  hybridization, a conformationally rigid protecting group bonded to the boron, and an organic group bonded to the boron through a boron-carbon bond. The organic group is chemically transformed, and the boron is not chemically transformed.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/190,223, filed Jul. 25, 2011, which is a divisional of U.S. patentapplication Ser. No. 11/937,338, filed Nov. 8, 2007, now U.S. Pat. No.8,013,203, which claims the benefit of U.S. Provisional PatentApplication No. 60/951,405 entitled “System for Controlling theReactivity of Boronic Acids” filed Jul. 23, 2007, each of which isincorporated herein by reference in its entirety.

BACKGROUND

The Suzuki-Miyaura reaction is a palladium- or nickel-catalyzed crosscoupling between a boronic acid or a boronic ester and an organohalideor an organo-pseudohalide. (Miyaura, A. Chem. Rev., 1995) This crosscoupling transformation is a powerful method for C—C bond formation incomplex molecule synthesis. The reaction is tolerant of functionalgroups, and has become increasingly general and widespread in its usefor coupling of organic compounds. (Barder, 2005; Billingsley, 2007;Littke, 2000; Nicolaou, 2005).

Boronic acids are notoriously sensitive to many common reagents. (Hall,2005; Tyrell, 2003) It is therefore typical to introduce the boronicacid functional group during the last step of a building blocksynthesis. However, many of the methods for doing so (hydroboration,trapping organometallic reagents with trimethylborate, etc.) areintolerant to a variety of common functional groups, such as alcohols,aldehydes, ketones, alkynes and olefins. This makes the synthesis ofstructurally complex boronic acid building blocks quite challenging. Incontrast, organostannanes are remarkably tolerant to a wide variety ofreaction conditions and are routinely carried through multiple steps enroute to structurally complex coupling partners. As a result,organostannanes have found widespread use in complex molecule synthesis(De Souza, M. V. N., 2006; Pattenden, G., 2002; Hong, B.-C., 2006)despite their well-known drawbacks including toxicity, high molecularweight, and byproducts that are difficult to remove. The ability tosimilarly carry protected boronic acids through multi-step syntheticsequences could substantially heighten their utility and broaden thescope of their applicability.

One area of research on the Suzuki-Miyaura reaction is the developmentof protecting groups for the boronic acid functional group. A compoundthat includes a protected boronic acid and another functional group canundergo chemical transformations of the other functional group withoutchemically transforming the boron. Removal of the protecting group(deprotection) then provides the free boronic acid, which can undergo aSuzuki-Miyaura reaction to cross-couple the compound with anorganohalide or an organo-pseudohalide.

In one example of a boronic acid protecting group, each of the two B—OHgroups is converted into a boronic ester group (>B—O—R) or a boronicamide group (>B—NH—R), where R is an organic group. The organic groupcan be removed by hydrolysis to provide the free boronic acid. Currentdata suggest that transmetalation between boronic acids and Pd(II)requires formation of an electronically-activated anionic boron ‘ate’complex and/or a hydroxo p₂-bridged organoboronate-Pd(II) intermediate.Both mechanisms require a vacant boron p-orbital that is Lewis acidic.Bidentate ligands that contain strongly electron-donating heteroatomsare known to inhibit the cross-coupling of organoboron compounds,presumably by reducing the Lewis acidity of the sp²-hybridized boroncenter. Harnessing this effect, a few selective cross-couplings withboron-protected organoboranes that contain halogens have been reportedrecently. (Deng, 2002; Hohn, 2004; Holmes, 2006; Noguchi, 2007) Examplesof protecting groups used in these selective reactions include pinacolesters (boronic ester) and 1,8-diaminonaphthalene (boronic amide). Theheteroatom-boron bonds in these protected compounds tend to be verystrong, however. The relatively harsh conditions required for cleavingthese ligands typically are incompatible with complex moleculesynthesis.

In another example of a protected boronic acid, the boron containingcompound is converted into a tetracoordinate anion, such as [R—BF₃]⁻,where R represents an organic group. Compounds containing theseprotecting groups are present as salts with a counterion, such as K⁺ orNa⁺. These anionic compounds are reported to be effective for inhibitingthe reaction of boron during chemical transformations such asnucleophilic substitution, 1,3-dipolar cycloaddition, metal-halogenexchange, oxidation, epoxidation, dihydroxylation, carbonylation, andalkenation (Wittig or Horner-Wadsworth-Emmons reactions). (Molander,2007) The boron itself is not protected from the Suzuki-Miyaurareaction, but can be used directly in the coupling transformation.Another class of tetracoordinate boron anions, [R—B(OH)₃]⁻, has beenreported in the context of purifying boronic acids for use in theSuzuki-Miyaura reaction. (Cammidge, 2006) As with the trifluoroboronateanion, the trihydroxyboronate anion is reactive in the Suzuki-Miyaurareaction.

These typical protection strategies for boronic acids each have somedisadvantages. Boronic esters and boronic amides can protect the boronfrom a wide variety of reaction conditions, including Suzuki-Miyaurareaction conditions. However, the harsh conditions required fordeprotection of boronic esters and boronic amides can cause undesirableside reactions with other functional groups. Trifluoroboronate anionsalso are unreactive in a wide variety of reaction conditions. However,this protection strategy does not allow for selective Suzuki-Miyaurareactions, since both protected and unprotected boron atoms will beeliminated in the coupling transformation.

It would be desirable to protect boronic acid groups in a wide varietyof synthetic reactions, including the Suzuki-Miyaura reaction. Ideally,protected boronic acids would undergo deprotection under mild conditionswith high yields. Such a system for controlling the reactivity ofboronic acids could greatly expand the versatility of the Suzuki-Miyaurareaction or of other reactions of boronic acids.

SUMMARY

In one aspect, the invention provides a protected organoboronic acidincluding a boronate group and an organic group. The boronate groupincludes a boron having an sp³ hybridization and a conformationallyrigid protecting group bonded to the boron. The organic group is bondedto the boron through a boron-carbon bond. The organic group is notselected from the group consisting of —C₂H₅, —C(CH₃)₂CH(CH₃)₂,cyclopentyl, tetrahydropyranyl, norbornyl,2,4,4-trimethyl-bicyclo[3.1.1]heptanyl, —C₆H₅, —C₆H₄—CH₃, —C₆H₄—CHO,—C₆H₄—OCH₃, —C₆H₄—F, —C₆H₄—Cl, —C₆H₄—Br, —C₆H₄—CF₃, and —C₆H₄—NO₂.

In another aspect, the invention provides a protected organoboronicacid, selected from the group consisting of protected organoboronicacids 8 d, 8 e, 8 f, 8 e, 9 a, 9 b, 9 c, 9 d, 9 e, 9 f, 13, 14, 16, 17,19, 20, 21, 22, 23, 24, 25, 26, 27, 30, 54 a, 54 b, 54 c, 54 d, 61, 64,66, 68, 70, 72, 74, 75, 80, 84, 91, 94, 302, and 306.

In yet another aspect, the invention provides a method of performing achemical reaction, including contacting a protected organoboronic acidwith a reagent, the protected organoboronic acid including a boronategroup and an organic group. The boronate group includes a boron havingan sp³ hybridization and a conformationally rigid protecting groupbonded to the boron. The organic group is bonded to the boron through aboron-carbon bond. The organic group is chemically transformed, and theboron is not chemically transformed.

In yet another aspect, the invention provides a method of performing achemical reaction, including contacting a protected organoboronic acidand an organohalide with a palladium catalyst, in the presence ofaqueous base, to provide a cross-coupled product. The protectedorganoboronic acid including a boronate group and an organic group. Theboronate group includes a boron having an sp³ hybridization and aconformationally rigid protecting group bonded to the boron. The organicgroup is bonded to the boron through a boron-carbon bond.

In yet another aspect, the invention provides a method of forming aprotected organoboronic acid, including reacting a compound representedby formula (I)

R¹—B(OH)₂  (I);

with a protecting reagent. The compound represented by formula (I) maybe formed in situ.

In yet another aspect, the invention provides a method of forming aprotected organoboronic acid, including reacting a compound representedby formula (XII)

with a N-substituted imino-di-carboxylic acid. The compound representedby formula (XII) may be formed in situ.

In yet another aspect, the invention provides a method of forming aprotected organoboronic acid, including reacting a compound representedby formula (XIII)

R¹⁰—BX₂  (XIII);

with a protecting reagent. The protecting reagent may includeN-methyliminodiacetic acid.

The following definitions are included to provide a clear and consistentunderstanding of the specification and claims.

The term “organoboronic acid” means a compound represented by formula(I):

R¹—B(OH)₂  (I),

where R¹ is an organic group that is bonded to the boron through aboron-carbon bond.

The term “group” means a linked collection of atoms or a single atomwithin a molecular entity, where a molecular entity is anyconstitutionally or isotopically distinct atom, molecule, ion, ion pair,radical, radical ion, complex, conformer etc., identifiable as aseparately distinguishable entity. The description of a group as being“formed by” a particular chemical transformation does not imply thatthis chemical transformation is involved in making the molecular entitythat includes the group.

The term “organic group” means a group containing at least one carbonatom.

The term “protected organoboronic acid” means a chemical transform of anorganoboronic acid, in which the boron has a lower chemical reactivityrelative to the original organoboronic acid.

The term “chemical transform” of a substance means a product of achemical transformation of the substance, where the product has achemical structure different from that of the substance.

The term “chemical transformation” means the conversion of a substanceinto a product, irrespective of reagents or mechanisms involved.

The term “sp³ hybridization” means that an atom is bonded and/orcoordinated in a configuration having a tetrahedral character of atleast 50%. For tetracoordinate boron atoms, the tetrahedral character ofthe boron atom is calculated by the method of Hopfl, H., J. Organomet.Chem. 581, 129-149, 1999. In this method, the tetrahedral character isdefined as:

THC_(DA)[%]=100×[1−(Σ_(n=1-6)|109.5−θ_(n)|°/90°)]

where θ_(n) is one of the six bond angles of the boron atom.

The term “protecting group” means an organic group bonded to at leastone atom, where the atom has a lower chemical activity than when it isnot bonded to the protecting group. For boron containing compounds, theterm excludes non-organic groups used to lower the chemical activity ofthe boron, such as the F⁻ and OH⁻ ligands of —BF₃ ⁻ and —B(OH)₃ ⁻.

The term “conformationally rigid protecting group” means an organicprotecting group that, when bonded to a boron atom, is determined to beconformationally rigid by the “conformational rigidity test”.

The term “alkyl group” means a group formed by removing a hydrogen froma carbon of an alkane, where an alkane is an acyclic or cyclic compoundconsisting entirely of hydrogen atoms and saturated carbon atoms. Analkyl group may include one or more substituent groups.

The term “heteroalkyl group” means a group formed by removing a hydrogenfrom a carbon of a heteroalkane, where a heteroalkane is an acyclic orcyclic compound consisting entirely of hydrogen atoms, saturated carbonatoms, and one or more heteroatoms. A heteroalkyl group may include oneor more substituent groups.

The term “alkenyl group” means a group formed by removing a hydrogenfrom a carbon of an alkene, where an alkene is an acyclic or cycliccompound consisting entirely of hydrogen atoms and carbon atoms, andincluding at least one carbon-carbon double bond. An alkenyl group mayinclude one or more substituent groups.

The term “heteroalkenyl group” means a group formed by removing ahydrogen from a carbon of a heteroalkene, where a heteroalkene is anacyclic or cyclic compound consisting entirely of hydrogen atoms, carbonatoms and one or more heteroatoms, and including at least onecarbon-carbon double bond. A heteroalkenyl group may include one or moresubstituent groups.

The term “alkynyl group” means a group formed by removing a hydrogenfrom a carbon of an alkyne, where an alkyne is an acyclic or cycliccompound consisting entirely of hydrogen atoms and carbon atoms, andincluding at least one carbon-carbon triple bond. An alkynyl group mayinclude one or more substituent groups.

The term “heteroalkynyl group” means a group formed by removing ahydrogen from a carbon of a heteroalkyne, where a heteroalkyne is anacyclic or cyclic compound consisting entirely of hydrogen atoms, carbonatoms and one or more heteroatoms, and including at least onecarbon-carbon triple bond. A heteroalkynyl group may include one or moresubstituent groups.

The term “aryl group” means a group formed by removing a hydrogen from aring carbon atom of an aromatic hydrocarbon. An aryl group may bymonocyclic or polycyclic and may include one or more substituent groups.

The term “heteroaryl group” means a group formed by replacing one ormore methine (—C═) and/or vinylene (—CH═CH—) groups in an aryl groupwith a trivalent or divalent heteroatom, respectively. A heteroarylgroup may by monocyclic or polycyclic and may include one or moresubstituent groups.

The term “substituent group” means a group that replaces one or morehydrogen atoms in a molecular entity.

The term “halogen group” means —F, —Cl, —Br or —I.

The term “organohalide” means an organic compound that includes at leastone halogen group.

The term “haloorganoboronic acid” means an organoboronic acid in whichthe organic group bonded to the boron through a boron-carbon bondincludes a halogen group or a pseudohalogen group.

The term “pseudohalogen group” means a group that has chemicalreactivity similar to that of a halogen group. Examples of pseudohalogengroups include triflate (—O—S(═O)₂—CF₃), methanesulfonate(—O—S(═O)₂—CH₃), cyanate (—C≡N), azide (—N₃) thiocyanate (—N═C═S),thioether (—S—R), anhydride (—C(═O)—O—C(═O)—R), and phenyl selenide(—Se—C₆H₅).

The term “organo-pseudohalide” means an organic compound that includesat least one pseudohalogen group.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdrawings and description. The components in the figures are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1 represents a method of forming a protected organoboronic acid.

FIG. 2A represents a method of performing a chemical reaction.

FIG. 2B represents a method of performing a chemical reaction.

FIG. 3 represents an X-ray crystal structure of an example of aprotected organoboronic acid.

FIG. 4 represents chemical structures, reaction schemes and productratios for an example of a reaction of protected and unprotectedorganoboronic acids in a Suzuki-Miyaura transformation.

FIG. 5 represents chemical structures, reaction schemes and reactionyields for examples of the preparation of protected haloorganoboronicacids.

FIG. 6 represents chemical structures, reaction schemes and reactionyields for (a) the reaction of examples of protected organoboronic acidshaving halogen groups with unprotected boronic acids and (b) thedeprotection of the coupled biaryl compounds.

FIG. 7A represents a variety of chemical transformations of the organicgroup of protected organoboronic acids.

FIG. 7B represents chemical structures, reaction schemes and reactionyields for the treatment of a free boronic acid, and of a variety of itsprotected analogues, with “Jones reagents”.

FIG. 8 represents an example of a reaction of a protected organoboronicacid in the Suzuki-Miyaura transformation under aqueous basicconditions.

FIG. 9 represents an example scheme for the retrosyntheticfragmentation, of ratanhine.

FIG. 10 represents the synthetic steps in an example of a totalsynthesis of ratanhine.

FIG. 11 represents a scheme for an example of the synthesis of polyenes.

FIG. 12 represents an example of a reaction of protected and unprotectedalkenyl organoboronic acids in a Suzuki-Miyaura transformation.

FIG. 13 represents an example of the formation of a protectedhaloorganoboronic acid.

FIG. 14 represents an example of the formation of a protectedhaloorganoboronic acid.

FIG. 15 represents an example of an iterative polyene synthesis usingprotected haloorganoboronic acids.

FIG. 16 represents an example of the formation of a protectedhaloorganoboronic acid.

FIG. 17 represents a variety of chemical transformations of the organicgroup of an example of a protected haloorganoboronic acid.

FIG. 18 represents an example of polyene synthesis using a protectedhaloorganoboronic acid.

FIG. 19 represents chemical structures, reaction schemes and reactionyields for the synthetic steps in an example of the total synthesis ofall-trans-retinal.

FIG. 20 represents structures and reaction schemes for the synthesis ofhalf of the AmB skeleton.

FIG. 21 represents structures and reaction schemes for the synthesis ofβ-parinaric acid.

FIG. 22 represents chemical structures, reaction schemes and reactionyields for the in situ cross-coupling of protected organoboronic acidswith an aryl halide.

FIG. 23 represents structures and reaction schemes for the preparationof protected organoboronic acids without the formation of thecorresponding free boronic acid.

FIG. 24 represents structures and reaction schemes for a cross-couplingreaction of three separate components, carried out in a single reactionmixture.

FIGS. 25A-B represent examples of protected haloorganoboronic acidbuilding blocks.

FIG. 26 represents examples of bis-boronate building blocks.

FIGS. 27A-B represent examples of protected organoboronic acid buildingblocks in which the organic group includes a functional group.

FIG. 28 represents examples of protected organoboronic acid buildingblocks.

DETAILED DESCRIPTION

The present invention makes use of the discovery that organoboronicacids can be protected from a variety of chemical reactions bytransformation into a protected organoboronic acid that includes a boronhaving an sp³ hybridization and a conformationally rigid protectinggroup bonded to the boron. A protected organoboronic acid including aboron having sp³ hybridization and a conformationally rigid protectinggroup bonded to the boron may be protected from cross-coupling with anorganohalide or an organo-pseudohalide through the Suzuki-Miyauratransformation. Moreover, the protected organoboronic acid may bedeprotected under mild reaction conditions with high yields, to providethe free organoboronic acid.

A protected organoboronic acid includes a boron having an sp³hybridization, a conformationally rigid protecting group bonded to theboron, and an organic group. The organic group is bonded to the boronthrough a boron-carbon (B—C) bond. The protecting group may be atrivalent group. Preferably, the organic group can undergo a chemicaltransformation without chemically transforming the boron.

FIG. 1 represents a method of forming a protected organoboronic acid,where organoboronic acid 100, having an sp² hybridization, undergoes aprotection transformation to form protected organoboronic acid 120,having an sp³ hybridization. As shown in FIG. 1, the protectedorganoboronic acid 120 can undergo a deprotection transformation to formorganoboronic acid 100, which includes a free boronic acid group. Incontrast to a protected organoboronic acid that includes a boron havingan sp³ hybridization and a conformationally rigid protecting groupbonded to the boron, conventional protected organoboronic acids includeeither a boron having an sp² hybridization, a boron present in ananionic compound, or a boron bonded to a protecting group that is notconformationally rigid.

In one example, a protected organoboronic acid may be represented byformula (II):

R¹—B-T  (II),

where R¹ represents an organic group bonded to the boron through a B—Cbond, B represents a boron having sp³ hybridization, and T represents aconformationally rigid protecting group. The R¹ group may be an alkylgroup, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, analkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group,or a combination of at least two of these groups. Moreover, R¹ mayinclude one or more substituent groups, which may include a heteroatombonded to a carbon of the alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, aryl, and/or heteroaryl group.

The R¹ group may include one or more functional groups. Preferably, R¹includes one or more other functional groups that can undergo a chemicaltransformation without chemically transforming the boron. Examples offunctional groups that may be present as part of R¹ include halogen orpseudohalogen (—X), alcohol (—OH), aldehyde (—CH═O), ketone (>C(═O)),carboxylic acid (—C(═O)OH), thiol (—SH), sulfone, sulfoxide, amine,phosphine, phosphite, phosphate, and combinations of these. Moreover,examples of functional groups that may be present as part of R¹ includemetal-containing groups, such as groups that contain metals such as tin(Sn), zinc (Zn), silicon (Si), boron, and combinations of these.Examples of organic groups that include functional groups and that maybe present in a protected organoboronic acid are listed in Table 1:

TABLE 1 Organic groups containing other functional groups in selectedprotected organoboronic acids R¹ is an alkyl group —(CH₂)₆—OH R¹ is analkenyl group * —CH═CH(CH₂)₄—OH —CH═CH—CH═CH—Cl —CH═CH—Br—CH═CH—CH═C(CH)₃—Cl —CH═C(CH)₃—Br —CH═CH—C(CH)₃═CH—Cl —C(CH)₃═CH—Br—(CH═CH)₃—Cl —C(CH)₃═C(CH)₃—Br —C(CH₃)═CH—(CH═CH)₂—Cl —C(CH)₃═C(CH)₃—Cl—C(CH₃)═CH—CH═CH—C(CH₃)═CH—Cl R¹ is an aryl group —C₆H₄—F —C₆H₄—CH(═O)—C₆H₄—Cl —C₆H₄—C(═O)OH —C₆H₄—Br R¹ is a heteroaryl group

R¹ is a combination of an alkyl or alkenyl group, with an aryl orheteroaryl group —C₆H₄—CH₂—OH —C₆H₄—CH═CH—I * —C₆H₄—CH₂—I

* May be cis- or trans- (or E- or Z-) isomer.Additional examples of organic groups including functional groups thatmay be present in a protected organoboronic acid are illustrated ordescribed throughout the present application.

Examples of functional groups that may be present as part of R¹ includeprotected alcohols, such as alcohols protected as silyl ethers, forexample trimethylsilyl ether (TMS), t-butyldiphenylsilyl ether (TBDPS),t-butyldimethylsilyl ether (TBDMS), triisopropylsilyl ether (TIPS);alcohols protected as alkyl ethers, for example methoxymethyl ether(MOM), methoxyethoxymethyl ether (MEM), p-methoxybenzyl ether (PMB),tetrahydropyranyl ether (THP), methylthiomethyl ether; alcoholsprotected as carbonyl groups, such as acetate or pivaloylate. Examplesof functional groups that may be present as part of R¹ include protectedcarboxylic acids, such as carboxylic acids protected as esters, forexample methyl ester, t-butyl ester, benzyl ester and silyl ester.Examples of functional groups that may be present as part of R¹ includeprotected amines, such as amines protected as carbamates, for exampleN-(trimethylsilyl)ethoxycarbamate (Teoc), 9-fluorenylmethyl carbamate(FMOC), benzylcarbamate (CBZ), t-butoxycarbamate (t-BOC); and aminesprotected as benzylamines.

In another example, a protected organoboronic acid may be represented byformula (II), where the R¹ group is represented by formula (III):

Y—R²—(R³)_(m)—  (III),

where Y represents a halogen group or a pseudohalogen group; R²represents an aryl group or a heteroaryl group; R³ represents an alkylgroup, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, analkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group,or a combination of at least two of these groups; and m is 0 or 1. R²may be, for example, a heteroaryl group. Moreover, R² and R³independently may include one or more substituent groups, which mayinclude a heteroatom bonded to a carbon of the R² or R³ group. The R²and R³ groups independently also may include one or more functionalgroups, as described for R¹ above.

In this example, the protected organoboronic acid is a protectedhaloorganoboronic acid. The Y— group may undergo Suzuki-Miyauracross-coupling with a compound that includes a free boronic acid,without reaction of the boron of the protected organoboronic acid.Deprotection of the boron provides the free boronic acid, which may thenundergo Suzuki-Miyaura cross-coupling with a compound that includes ahalogen group or a pseudohalogen group. These protectedhaloorganoboronic acids may thus be used as bifunctional building blocksfor iterative synthesis through selective Suzuki-Miyauratransformations.

In one example, a protected organoboronic acid may include a boronhaving an sp³ hybridization, a conformationally rigid protecting groupbonded to the boron, and an organic group bonded to the boron through aboron-carbon (B—C) bond, where the organic group is not one of thegroups listed in Table 2, below. The protecting group may be a trivalentgroup.

TABLE 2 Organic groups in selected protected organoboronic acidscyclopentyl;

—C₂H₅ —C(CH₃)₂CH(CH₃)₂ norbornyl;

—C₆H₅ —C₆H₄—CH₃ —C₆H₄—OCH₃ tetrahydropyranyl;

—C₆H₄—CHO —C₆H₄—F 2,4,4-trimethyl- bicyclo[3.1.1] heptanyl;

—C₆H₄—Cl —C₆H₄—Br —C₆H₄—CF₃ —C₆H₄—NO₂

In another example, a protected organoboronic acid may include a boronhaving an sp³ hybridization, a conformationally rigid protecting groupbonded to the boron, and an organic group bonded to the boron through aboron-carbon (B—C) bond, where the organic group is not one of thegroups listed in Table 2 or in Table 3, below. The protecting group maybe a trivalent group.

TABLE 3 Organic groups in selected protected organoboronic acids—C₆H₄—C₆H₄—CH₃ -4-bromothiophenyl -4-tolyl-thiophenyl-cyclopropyl-C₆H₄—Br -cyclopropyl-C₆H₄—C₆H₄—CH₃ —CH═CH—C₆H₄—Br—CH═CH—C₆H₄—C₆H₄—CH₃ -5-bromo-2-benzofuranyl-2-methoxymethoxy-4-methoxy- -5-(1-propenyl)-2-benzofuranyl5-(5-(1-propenyl)-2- -2-methoxymethoxy-4-methoxy- benzofuranyl)phenyl5-bromophenyl

In this example, the protected organoboronic acid may be represented byformula (IV):

R⁴—(R⁵)_(m)—B-T  (IV),

where R⁴ and R⁵ together represent the organic group, m is 0 or 1, Trepresents a conformationally rigid protecting group, and B representsthe boron having sp³ hybridization. The R⁴ and R⁵ groups independentlymay be an alkyl group, a heteroalkyl group, an alkenyl group, aheteroalkenyl group, an alkynyl group, a heteroalkynyl group, an arylgroup, a heteroaryl group, or a combination of at least two of thesegroups. Preferably, in this example, R⁴ is not an aryl group thatincludes a halogen substituent group or a pseudohalogen substituentgroup. For example, R⁴ may be an alkyl group, a heteroalkyl group, analkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynylgroup or a heteroaryl group, and may include a halogen substituent groupor a pseudohalogen substituent group. For example, R⁴ may be a groupthat does not contain a halogen or a pseudohalogen group, and mayfurther be an aryl group.

In formulas (II) and (IV), the group T represents a conformationallyrigid protecting group bonded to the boron. Conformational rigidity ofan organic protecting group bonded to a boron atom is determined by thefollowing “conformational rigidity test”. A 10 milligram (mg) sample ofa compound including a boron atom and an organic protecting group bondedto the boron is dissolved in dry d₆-DMSO and transferred to an NMR tube.The sample is then analyzed by ¹H-NMR at temperatures ranging from 23°C. to 150° C. At each temperature, the sample shim is optimized, and a¹H-NMR spectrum obtained. If the protecting group is notconformationally rigid, then split peaks for a set of diastereotopicprotons in the ¹H-NMR spectrum obtained at 23° C. will coalesce into asingle peak in the ¹H-NMR spectrum obtained at 100° C. If the protectinggroup is conformationally rigid, then split peaks for a set ofdiastereotopic protons in the ¹H-NMR spectrum obtained at 23° C. willremain split, and will not coalesce into a single peak in the ¹H-NMRspectrum obtained at 90° C. An example of this test is provided inExample 10 below.

In one example of a protected organoboronic acid that includes aconformationally rigid protecting group bonded to the boron, a protectedorganoboronic acid may be represented by formula (X):

where R¹⁰ represents an organic group, B represents a boron having sp³hybridization, and R²⁰, R²¹, R²², R²³ and R²⁴ independently are ahydrogen group or an organic group. R²⁰, R²¹, R²², R²³ and R²⁴independently may be an alkyl group, a heteroalkyl group, an alkenylgroup, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group,an aryl group, a heteroaryl group, or a combination of at least R²², R²³and two of these groups. In one example, R²⁰ is methyl, and each of R²¹,R²², R²³ and R²⁴ is hydrogen. The protected organoboronic acid of thisexample may be represented by formula (XI):

where R¹⁰ represents the organic group, and B represents the boronhaving sp³ hybridization. The R¹⁰ group may be an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, a heteroaryl group, or acombination of at least two of these groups, as described for R¹, above.The R¹⁰ group may include one or more substituent groups, and/or one ormore functional groups.

Protected organoboronic acids according to formula (X) may be preparedby reaction of an appropriate N-substituted imino-di-carboxylic acidwith the corresponding unprotected boronic acid (XII), as illustrated inthe following reaction scheme:

In a specific example, protected organoboronic acids according toformula (XI) may be prepared by reaction of N-methyliminodiacetic acid(MIDA) with the corresponding unprotected boronic acid (XII), asillustrated in the following reaction scheme:

In each case, the protected organoboronic acid may be deprotected bycontact with a mild aqueous base, to provide the free boronic acid(XII).

Protected organoboronic acids according to formula (X) also may beprepared without using an isolated boronic acid as a reactant. Theboronic acid may be formed in situ, just prior to its conversion to aprotected organoboronic acid. Protected organoboronic acids also may beformed without ever forming the free boronic acid. FIG. 23 showsstructures and reaction schemes for the preparation of protectedorganoboronic acids without the formation of the corresponding freeboronic acid. Experimental details are provided in Example 20.

In one example, the boronic acid may be produced in situ, such as byhydrolysis of a boronate ester (i.e. R¹⁰—B—(OR′)(OR″), R′ and R″ areorganic groups). The boronate ester may be formed, for example, byaddition of HB(OR′)(OR″) across the C—C multiple bond of an alkene or analkyne. (Brown, 1972) The boronate ester also may be formed, forexample, by a Miyaura borylation (Miyaura, 1997; Miyaura, JOC, 1995); byreaction of an organohalide with an organolithium reagent, followed byreaction with boronate triester (i.e. B(OR)₃); or by reaction of aboronate triester with an organometal reagent (i.e. R¹⁰—Li, R—Mg, R—Zn;Brown, 1983). In another example, the boronic acid may be produced insitu, such as by treatment of a tri-substituted borane (i.e. R¹⁰—BR′R″)with acetaldehyde (R′ and R″ are organic groups). The tri-substitutedborane may be formed, for example, by hydroborylation of an alkene or analkyne with HBR′R″, to add the HBR′R″ across the C—C multiple bond.

In another example, a boronic halide (XIII) may be reacted with a diacidor its corresponding salt to provide protected organoboronic acid (X),as illustrated in the following reaction scheme:

The boronic halide may be formed by hydroborylation of an alkene or analkyne with HBX₂ (Brown, 1984; Brown, 1982) or with BX₃ (Soundararajan,1990). The boronic halide also may be formed by treatment of a silanesuch as R¹⁰—SiR₃ with BBr₃. (Qin, 2002; Qin, 2004)

Protected organoboronic acids including a MIDA boronate ester protectinggroup are readily purified by column chromatography. This is unusual forboronic acids, which are typically unstable to chromatographictechniques. These compounds also may be highly crystalline, whichfacilitates purification, utilization, and storage. These compounds areextremely stable to long term storage, including storage on the benchtop under air. This is also unusual, as many boronic acids are unstableto long term storage.

Protected organoboronic acids including a boron having an sp³hybridization, a conformationally rigid protecting group bonded to theboron, and an organic group may be useful as synthetic building blocks.Examples of building blocks include protected haloorganoboronic acids,such as those listed in FIG. 25. Examples of building blocks includebis-boronates having a first boron atom having an sp³ hybridization anda conformationally rigid protecting group bonded to the first boronatom, and a second boron atom that may be present as a boronic acid oras a different type of protected boron. Examples of bis-boronatesinclude those listed in FIG. 26, and derivatives of these bis-boronatesin which the second boron atom is present as a boronic acid, a boronicester (including a pinacol ester), —BF₃ ⁻ or —B(OH)₃ ⁻. Examples ofbuilding blocks include protected organoboronic acids in which theorganic group includes a functional group, such as those listed in FIG.27. Examples of other miscellaneous building blocks are listed in FIG.28. The protecting group in each of these building blocks is representedas the MIDA boronate ester. Protected organoboronic acid building blocksmay also include compounds having one or more substitutent groups on theprotecting group, and/or having a different group bonded to the nitrogenof the protecting group. For example, the protecting groups in thesebuilding blocks may be a protecting group as described for formula (X).

Protected organoboronic acids including a MIDA boronate ester protectinggroup have a number of advantageous properties. The MIDA group istypically effective in decreasing the reactivity of the boronic acid towhich it is esterified. One possible explanation for this decrease inreactivity is that a vacant, Lewis acidic boron p-orbital is notavailable to react with other substances. For example, the protectedboron no longer has a vacant, Lewis acidic p-orbital to complex with thepalladium catalyst involved in the Suzuki-Miyaura transformation. Thus,this protection strategy should decrease the reactivity of any boronicacid, including its reactivity toward the Suzuki-Miyaura transformation.In addition, the MIDA boronate ester group seems to be stable to a widevariety of reaction conditions, besides cross-coupling. This stabilitymay facilitate their utilization in the synthesis of complex syntheticbuilding blocks that contain boronic acid functional groups.

Although these sp³-hybridized boronate esters having a conformationallyrigid protecting group bonded to the boron are protected from anhydrousSuzuki-Miyaura coupling even at 80° C. for 28 hours, deprotection can bereadily achieved at 23° C. using extremely mild aqueous basicconditions. One example of deprotection conditions is treatment with 1molar (M) aqueous sodium hydroxide (NaOH) in tetrahydrofuan (THF) for 10minutes. Another example of deprotection conditions is treatment withsaturated aqueous sodium bicarbonate (NaHCO₃) in methanol (MeOH) for 6hours. These mild conditions are in contrast to typical protectinggroups based on boronate esters, which can require harsh cleavageconditions.

FIG. 2A represents a method 200 of performing a chemical reaction,including contacting 220 a protected organoboronic acid 204 with areagent, where the organic group is chemically transformed, and theboron is not chemically transformed. Protected organoboronic acid 206 isa chemical transform of protected organoboronic acid 204 in which R^(A)has been transformed into R^(B), but the boron has not been chemicallytransformed. The method optionally includes forming the protectedorganoboronic acid 204 by reacting 210 a boronic acid 202 with aprotecting reagent. The protected organoboronic acid 204 may also beformed without forming and/or isolating the boronic acid 202. The methodoptionally includes deprotecting 230 the protected organoboronic acid206 to form boronic acid 208.

FIG. 2B represents a method 250 of performing a chemical reaction,including reacting 260 the protected organoboronic acid 204 with anorganohalide 252, to provide the cross-coupled product 254. The reacting260 may include contacting the protected organoboronic acid 204 andorganohalide 252 with a palladium catalyst in the presence of aqueousbase. The protecting group may be cleaved in situ, providing the freeboronic acid (i.e. 202 in FIG. 2A), which can then cross-couple with theorganohalide 252. Thus, in addition to serving as protected buildingblocks during complex synthesis, the protected organoboronic acids canbe useful as stable, pure derivatives of boronic acids.

The protected organoboronic acid 204 includes a boron having an sp³hybridization, a conformationally rigid protecting group, and an organicgroup R¹ bonded to the boron through a B—C bond. The protectedorganoboronic acid 204 may be any of the protected organoboronic acidsdisclosed above. Preferably the protected organoboronic acid 204includes a trivalent protecting group bonded to the boron.

The protected organoboronic acid 204 may be, for example, represented byformula (II), as described above. For example, the protectedorganoboronic acid 204 may be represented by formula (II), where the R¹group is represented by formula (III), as described above. The protectedorganoboronic acid 204 may be, for example, represented by formula (IV),as described above. The protected organoboronic acid 204 may be, forexample, represented by formula (X) or (XI), as described above.

FIG. 3 is a representation of an X-ray crystal structure of an exampleof a protected organoboronic acid,(N→B)-tolyl[N-methyliminodiacetate-O,O′,N]borane 3 a. In this structure,the boron (B2) is shown to be sp³ hybridized, and is in a tetrahedralorientation.

FIG. 4 shows chemical structures, reaction schemes and product ratiosfor an example of a reaction of protected and unprotected organoboronicacids in a Suzuki-Miyaura transformation. Stoichiometric quantities ofpara-n-butylphenyl-boronic acid 2 and(N→B)-tolyl-[N-methyliminodiacetate-O,O′,N]borane 3 a were reacted with0.8 equiv. of p-bromobenzaldehyde under Buchwald's anhydrousSuzuki-Miyaura conditions. (Barder, 2005) A 24:1 ratio of biaryls 5 and6 was observed, consistent with strong preferential reactivity of thep-bromobenzaldehyde with the sp²-hybridized boronic acid 2 (entry 1). Incontrast, the control experiment with p-tolylboronic acid 3 b yielded a1:1 mixture of products (entry 2). Sterically bulky N-alkyl substitutionon the protecting group was tolerated, but was not significantlyadvantageous (entry 3). The N-methyl diethanolamine adduct 3 d, which isknown to be significantly less conformationally rigid than itsiminodiacetic acid counterpart, (Contreras, 1983) demonstrated noselectivity (entry 4). Experimental details for the preparation and useof these compounds are provided in Examples 1 and 2, respectively.

FIG. 5 shows chemical structures, reaction schemes and reaction yieldsfor examples of the preparation of protected haloorganoboronic acids. Avariety of haloboronic acids were complexed with MIDA to yield a seriesof B-protected bifunctional building blocks. All three positionalisomers of bromophenylboronic acid, as well as the heteroaromatic5-bromothiopheneboronic acid, reacted cleanly to generate 8 a-d inexcellent yields. The same complexation conditions yielded vinyl andalkyl boronate esters 8 e and 8 f. The pyramidalized nature of the(N→B)-vinyl-[N-methyliminodiacetate-O,O′,N]borane 8 e was confirmed viasingle crystal X-ray diffraction analysis. Remarkably, thesepyramidalized boronate esters were stable to and readily purified bysilica gel chromatography. All yields shown in FIG. 5 representmaterials isolated as analytically-pure, colorless crystalline solidsafter a single chromatographic step. Moreover, in stark contrast to thecorresponding boronic acids (Hall, 2005), all of these boronate esterswere indefinitely bench stable under air. Experimental details areprovided in Example 3.

FIG. 6 shows chemical structures, reaction schemes and reaction yieldsfor (a) the reaction of protected organoboronic acids having halogengroups with unprotected boronic acids and (b) the deprotection of thecoupled biaryl compounds to provide the free boronic acids. Thepotential of the MIDA ligand to enable selective cross-couplings wasprobed by reacting each of the B-protected bifunctional building blocksof Example 2 with p-tolylboronic acid. Although the reactivity of aryl,heteroaryl, vinyl, and alkylboronic acids can vary dramatically (Barder,2005; Billingsley, 2007; Littke, 2000; Nicolaou, 2005), the sameprotecting group was effective with all four classes of nucleophiles,yielding selective cross-coupling products 9 a-9 f. All four classes ofnucleophiles were also efficiently deprotected using a standard set ofmild aqueous basic conditions of 1 molar (M) aqueous NaOH in THF, at 23°C., for 10 minutes. Saturated aqueous NaHCO₃ was also effective (entry3). Experimental details are provided in Example 4.

FIG. 7A shows chemical structures, reaction schemes and reaction yieldsfor a variety of chemical transformations of protected organoboronicacids, where the organic group is chemically transformed, but the boronis not chemically transformed. The MIDA boronate esters were remarkablyrobust. In one example, protected organoboronic acid 19, MIDA-protectedp-hydroxymethyl-phenyl boronic acid, was smoothly transformed into thecorresponding aldehyde 20 via a Swern oxidation, and the reversetransformation was achieved with sodium borohydride.

In another example, treatment of 19 with the very strongly oxidizing andacidic “Jones reagents” (CrO₃ and concentrated H₂SO₄) unexpectedlyyielded benzoic acid derivative 21 without any observable decompositionof the protected organoboronic acid. This remarkable stability toextremely acidic conditions was very surprising, and contrasts sharplywith the pronounced lability of MIDA-based protected organoboronic acidto very mild aqueous base, such as aqueous NaHCO₃. However, manynon-aqueous bases seemed to be well-tolerated.

FIG. 7B shows chemical structures, reaction schemes and reaction yieldsfor the treatment of a free boronic acid, and of a variety of itsprotected analogues, with “Jones reagents”, using reaction conditionsidentical to those for the oxidation of 19 to 21. Reaction of the freeboronic acid 190 provided a mixture of benzoic acid and p-hydroxybenzoicacid, with complete removal of the boron from the p-benzyl alcoholorganic group. The protecting group for 191 was a pinacol ester group,where the boron was sp² hybridized. Protected analogue 192 included theboron as part of an anionic compound, specifically as an R—BF₃ ⁻ anion.The protecting group for 193 was a N-methyldiethanolamine ester, whichwas not a conformationally rigid protecting group (see Example 10,below). The reactions of protected analogues 191, 192 and 193 eachproduced a mixture of benzoic acid and p-hydroxybenzoic acid, withcomplete removal of the boron from the p-benzyl alcohol organic group.Thus the boron of the protected organoboronic acid 19, which included aconformationally rigid protecting group bonded to an sp³ hybridizedboron and an organic group bonded to the boron through a boron-carbonbond, was surprisingly and unexpectedly inert to the oxidizing andacidic conditions of “Jones reagents”.

Referring again to FIG. 7A, in another example, the protectedorganoboronic acid 19 was compatible with the carbanion-mediated Evans'aldol and HWE olefination reactions, yielding 22 and 23, respectively.The former also required a peroxide-mediated oxidative cleavage of theinitially-formed boron-alkoxide aldol adduct, to which the MIDA complexwas again surprisingly stable. In another example of a differentcarbon-carbon bond-forming reaction, the Takai olefination was alsocompatible with the protected organoboronic acid, providing a new way toaccess B-protected haloboronic acids such as 24.

In other examples, some common functional group transformations werealso well-tolerated by the protected organoboronic acid. Thesetransformations included alcohol silylation (25) and desilylation,p-methoxybenzylation with the extremely acidic catalyst TfOH (26), andiodination (27).

It has been demonstrated that a protected organoboronic acid, in whichthe organic group includes a boron that is not sp³ hybridized, canundergo chemical transformation of the non-sp³ hybridized boron withoutchemically transforming the boron having sp³ hybridization. See, forexample, FIG. 14. Thus, selective cross-coupling can be performed with adifferentially-ligated bis-boronate reagent.

It has also been demonstrated that a protected organoboronic acid canundergo a transmetalation reaction with a compound containing twodifferent types of metal atoms without chemically transforming theboron. See, for example, FIG. 15, which shows a Negishi cross-couplingbetween a protected haloorganoboronic acid and a bis-metallated vinylcompound including zinc and tin. Thus, a cross-coupling reaction can beperformed, in which the transformation is triply-metal selective (B, Sn,Zn).

FIG. 8 shows chemical structures, reaction schemes and reaction yieldsfor the reaction of a protected organoboronic acid in the Suzuki-Miyauratransformation under aqueous basic conditions. Protected organoboronicacid 30 reacted with methyl p-bromophenyl ketone in the presence of apalladium catalyst, to provide the cross-coupled product 32. Since thereaction was performed in the presence of aqueous base, the MIDAboronate ester was cleaved in situ, providing the free boronic acid.Thus, in addition to serving as protected building blocks during complexsynthesis, the protected organoboronic acids can be useful as stable,pure derivatives of boronic acids. As noted above, boronic acids can bedifficult to purify and can be unstable during long-term storage. Incontrast, protected organoboronic acids including a boron having sp³hybridization and having a conformationally rigid protecting groupbonded to the boron can be purified by crystallization and/orchromatography, and can be stable for long periods of time, even in air.

These reactions demonstrate some of the possible applications ofprotected organoboronic acids that include a boron having an sp³hybridization and having a conformationally rigid protecting groupbonded to the boron. These compounds may be used for simple, highlymodular syntheses of molecules through iterative Suzuki-Miyauracross-coupling transformations. These transformations may involvebifunctional building blocks, such as protected organoboronic acids thatinclude a halogen or a psuedohalogen group. For a given synthesis, allthe building blocks may be prepared having the required functionalgroups preinstalled in the correct oxidation state and with the desiredstereochemical relationships. These building blocks may then be broughttogether by the recursive application of one mild reaction, such as theSuzuki-Miyaura reaction. In addition to being very simple, efficient,and potentially amenable to automation, this strategy is inherentlymodular and thus well-suited for making collections of structuralderivatives.

This iterative cross-coupling strategy can dramatically simplify theprocess of small molecule synthesis. For example, the natural productratanhine has been prepared using the mild Suzuki-Miyaura reactioniteratively to bring together a collection of easily synthesized,readily purified, and highly robust building blocks. The synthesis wasshort and highly modular, and thus a variety of derivatives should bereadily accessible simply by substituting modified building blocks intothe same pathway.

FIG. 9 shows a scheme for the retrosynthetic fragmentation of ratanhine11 into four simpler building blocks 12-15 via recursive application ofthree Suzuki-Miyaura transforms. The natural product ratanhine is themost complex member of a large family of neolignans isolated from themedicinal plant Ratanhiae radix. (Arnone, 1990) There were severalchallenges associated with this plan that provided rigorous tests forthe protected organoboronic acids. For example, cross-coupling of arylboronic acids tends to be more facile than that of their vinylcounterparts (Barder, 2005), making the selective cross-coupling betweenvinyl boronic acid 12 and bromoarylboronate 13 unsecured. In addition,heteroaromatic boronic acids, such as the deprotected version of 13, canbe very sensitive to decomposition. (Tyrell, 2003) Moreover,cross-coupling with the highly electron-rich and sterically-encumberedaryl bromide 14 was expected to require elevated temperatures and/orlong reaction times that would test the limits of stability for the MIDAligand.

FIG. 10 shows chemical structures, reaction schemes and reaction yieldsfor the synthetic steps in the total synthesis of ratanhine.Experimental details are provided in Examples 6-9. Once building blocks13-15 were prepared (see Examples 6-8, respectively), the synthesiscommenced with a successful selective cross-coupling between vinylboronic acid 12 and bromoarylboronate 13 to yield intermediate 16.Strikingly, benzofuranylboronates 13 and 16 were bench stable under airfor at least one month. In contrast, the 2-benzofuranylboronic acid thatresulted from deprotection of 16 rapidly decomposed over the course of afew days. This challenge was overcome simply by deprotecting 16 justprior to cross-coupling with 14. As expected, this electron-rich andsterically-bulky aryl bromide 14 required both an elevated temperature(80° C., sealed tube) and extended reaction time (28 hours). Remarkably,the MIDA protective group was found to be completely stable to theseforcing conditions, yielding advanced intermediate 17. A final sequenceof B-deprotection, cross-coupling with 15, and cleavage of the two MOMethers completed the first total synthesis of ratanhine. This synthesisinvolved 7 steps in the longest linear sequence. All spectral data ofthe final product match that reported in Arnone (1990).

The class of small molecules collectively referred to as “polyenenatural products” are remarkably diverse in origin, being synthesized bybacteria, fungi, slime-moulds, plants, a wide range of aquatic species,and even animals. These compounds also represent an extraordinarydiversity of structures and functions, and may include a wide variety ofdouble bonds, such as E- and Z-1,2-disubstituted, trisubstituted, andtetrasubstituted olefins. Activities of these compounds includeantifungal, antibacterial, and antitumor properties, and many studiesshow that subtle modifications of these structures can have dramaticimpacts on their activities. Undoubtedly, polyene natural products havesubstantial untapped potential for improving human health, andunfettered synthetic access to these compounds and their derivatives isparamount for realizing this potential. Protected organoboronic acidsand their use in synthetic methods may provide a simple and modularassembly of a broad range of these targets through iterativecross-coupling.

The synthesis of polyenes is made challenging by the sensitivity ofconjugated double bond frameworks to many common synthetic reagents.Controlling the geometry of each double bond is also a critical issue.Many valuable methods have been developed, but synthetic strategiesbased on palladium-mediated cross-coupling are particularly attractivedue to the mild and stereospecific nature of these reactions. In thisvein, a variety of methods based on bis-metallated (Lhermitte, 1996;Lipshutz 1997; Pihko, 1999; Babudri, 1998; Murakami, 2004; Denmark,2005; Lipshutz, 2005; Coleman, 2005; Coleman, 2007) or bis-halogenated(Organ, 2000; Antunes, 2003; Organ, 2004) lynchpin reagents have beenreported. In these approaches, three fragments are brought togetherusing two cross-coupling reactions to engage the orthogonally-reactivetermini of the lynchpin. An important advantage of the iterativecross-coupling strategy using protected organoboronic acids including aboron having sp³ hybridization and having a conformationally rigidprotecting group bonded to the boron is the inherent potential forlimitless iteration. That is, all of the required building blocks can intheory be brought together via the recursive application of a single,mild reaction. This may dramatically simplify the synthesis process, andmay readily enable analog preparation. The use of only one reaction alsocan help to minimize the potential for incompatibilities between thefunctional groups appended to the building blocks and the reactionconditions used to couple them. In addition, the use of bifunctionalhaloorganoboronic acids can avoid toxic metals such as organostannes,which are frequently employed in bis-metallated lynchpin-type reagents.Finally, the protected haloorganoboronic acids tend to be free-flowingcrystalline solids that can be readily purified by silica gelchromatography and/or recrystallization and stored indefinitely on thebenchtop under air.

FIG. 11 shows a scheme for an example of the general application of theiterative cross-coupling strategy to the synthesis of polyenes,including polyene natural products. A polyene is a compound thatincludes at least two alternating carbon-carbon double bonds.Cross-coupling of protected haloorganoboronic acid 54 with boronic acid55 through the Suzuki-Miyaura reaction provides protected organoboronicacid 56. Deprotection of 56 provides the free boronic acid, which can becross-coupled with an organohalide or organopseudohalide. If theorganohalide or organopseudohalide includes a protected organoboronicacid, the polyene chain can be iteratively lengthened. In the example ofFIG. 11, addition of organohalide 57 after the deprotection providespolyene product 58.

FIG. 12 shows chemical structures, reaction schemes and product ratiosfor an example of a reaction of protected and unprotected alkenylboronicacids in a Suzuki-Miyaura transformation. N-Methyliminodiacetic acid wascomplexed with 1-hexenyl boronic acid to generate previously unknown(N→B)-(1-hexenyl)-[N-methyliminodiacetate-O,N]borane 54 d. Thisprotected organoboronic acid was studied by temperature dependent ¹H NMR(Mancilla, 2005), and the N→B bond was found to be stable up to at least110° C. Stoichiometric quantities of 1-propylene boronic acid 50 and(N→B)-(1-hexenyl)-[N-methyliminodiacetate-O,O′,N]borane 54 d werereacted with 0.8 equiv. of β-bromostyrene under Suzuki-Miyauracross-coupling conditions. A 75:1 mixture of products 51 and 52 wasobserved, consistent with a very high selectivity for coupling of theunprotected vinyl boronic acid 50.

FIGS. 13-18 shows chemical structures, reaction schemes and reactionyields for the preparation of protected haloorganoboronic acids 54 a, 54b and 54 c, and for subsequent reactions with 54 a and 54 c. Referringto FIG. 13, complexation of (E)-dibromo(2-bromovinyl)borane 59 with MIDAefficiently generated bifunctional olefin 54 a. This reaction wasreproduced on a 75 mmol scale to yield 12 g of 54 a as a free-flowingcrystalline solid that is stable to storage indefinitely under air.Experimental details are provided in Example 11.

Although Miyaura borylations with 1,2-disubstituted-vinyl halides arerare, 54 a was converted smoothly into the novel bis-borylated olefin 61(FIG. 14). An X-ray structure of 61 unambiguously confirmed the sp²- andsp³-hybridizations of the pinacol and MIDA boronate ester protectinggroups, respectively. A subsequent doubly-selective (metal and halogen)Suzuki-Miyaura cross-coupling between 61 and (E)-1-iodo-2-chloroethylene62 yielded the targeted diene 54 b. This reaction demonstrated aselective cross-coupling with a differentially-ligated bis-boronatereagent. Experimental details are provided in Example 12.

Referring to FIG. 15, Negishi cross-coupling between 54 a and thebis-metallated vinyl zinc 63 yielded the boronyl/stannyl diene 64. Thisreaction demonstrated a triply-metal selective (B, Sn, Zn)cross-coupling reaction. The targeted B-protected halotrienyl boronicacid 54 c was prepared by a subsequent metal and halogen selectivecross-coupling between 64 and 62. Experimental details are provided inExample 13.

Although this route was effective, organostannanes are toxic and itwould be preferable to prepare 54 c without the use of tin-containingintermediates. Thus, referring to FIG. 16, bis-borylated diene 66 willbe synthesized as an alternative, tin-free intermediate fortrienylchloride building block synthesis through Heck-type couplingbetween 54 a and vinylpinacolboronic ester 65 or through Miyauraborylation of 54 b.

Referring to FIG. 17, protected haloalkenylboronic acid 54 a hasundergone selective Suzuki-Miyaura, Stile, Heck, and Sonogashiracouplings to generate products 68, 70, 72, and 74, respectively.Protected organoboronic acid 80 was the product of Suzuki-Miyauracross-coupling. Experimental details are provided in Example 14.

Referring to FIG. 18, although cross-couplings with vinyl chlorides arerelatively rare, using Buchwald's electron-rich and sterically bulkyphosphine ligand 4 c has provided a very efficient coupling betweentrienylchloride 54 c and vinylboronic acid 55. Experimental details areprovided in Example 15.

FIG. 19 shows chemical structures, reaction schemes and reaction yieldsfor the synthetic steps in the total synthesis of all-trans-retinal. Theknown trienylboronic acid 83 (Uenishi, 2003) was selectively coupledwith bifunctional building block 54 a to yield tetraenylboronate ester84. Surprisingly, although boronic acid 83 is unstable to concentrationand storage, the more advanced MIDA boronate 84 was isolated as acrystalline solid via silica gel chromatography and was very stable tostorage. A final sequence of boronic acid deprotection andcross-coupling with aldehyde 85 (Romo, 1998) yielded the naturalproduct. Experimental details are provided in Example 16.

In contrast to most antibiotics which function via inhibition of mutablemacromolecular targets and are thus very susceptible to microbialresistance, the antimycotic agent amphotericin B (AmB) operates viaself-assembly with ergosterol in fungal lipid membranes to formpermeabilizing ion channels. Because of this lack of a mutable proteintarget, resistance to this broad-spectrum antifungal agent is extremelyrare despite more than four decades of widespread clinical use. However,due to competitive self-assembly with cholesterol to form relatedchannels in human cells, AmB is also very toxic which often limits itsclinical efficacy. The first, and at present only, reported totalsynthesis of AmB was accomplished by K. C. Nicolaou and coworkers in1986. (Nicolaou, 1987; Nicolaou, 1988) This synthesis required 59 stepsin the longest linear sequence, and some of the late-stagetransformations proceeded in very low yield. In addition to theseshortcomings, a lack of sufficient modularity and flexibility precludethe use of this synthesis for the practical preparation of structuralderivatives of AmB.

FIG. 20 shows structures and reaction schemes for the synthesis of halfof the AmB skeleton. Reaction of 1,3-hept-2-ene boronic acid 90 with BB₃yielded protected organoboronic acid 91, in which the organic group is apolyene. Deprotection of 91 with sodium hydroxide produces the freeboronic acid, which is reacted with BB₄ through a Suzuki-Miyauracross-coupling reaction, yielding polyene 92. This product correspondsto half of the skeleton of AmB. Experimental details are provided inExample 17.

Another interesting polyene, β-parinaric acid 96, has been used for morethan three decades as a fluorescent probe for membrane properties. Inaddition, related tetraenoic acids demonstrate remarkable aggregationbehaviors including the formation of antipodal chiral aggregates from asingle enantiomer. The utility of 96 and/or its analogs would benefitfrom more efficient and modular synthetic access to this class ofcompounds.

FIG. 21 shows structures and reaction schemes for the synthesis ofβ-parinaric acid 96. The protected chlorodienylboronic acid 54 b wasemployed in a modular, three-step synthesis of β-parinaric acid fromreadily-available starting materials. Specifically, using a modificationof the newly identified conditions for polyenylchloride cross-coupling,a selective pairing between the bifunctional dienylchloride 54 b and(E)-1-butenylboronic acid 93 yielded the all-trans trienyl boronate 94.This protected organoboronic acid was stable to purification by columnchromatography. Deprotection of 94 was achieved under mild aqueous basicconditions, and subsequent cross-coupling with vinyl iodide 95 yieldedβ-parinaric acid 96 as a fluorescent solid. Experimental details areprovided in Example 18.

FIG. 22 shows chemical structures, reaction schemes and reaction yieldsfor the in situ cross-coupling of protected organoboronic acids with anaryl halide. In this example, the protected organoboronic acids functionas surrogates for the corresponding boronic acids. The correspondingboronic acid are difficult to purify. Experimental details are providedin Example 19.

The following examples are provided to illustrate one or more preferredembodiments of the invention. Numerous variations may be made to thefollowing examples that lie within the scope of the invention.

EXAMPLES General Methods

Commercial reagents were purchased from Sigma-Aldrich (St. Louis, Mo.),Fisher Scientific (Waltham, Mass.), Alfa Aesar/Lancaster Synthesis (WardHill, Mass.), or Frontier Scientific (Logan, Utah), and were usedwithout further purification unless otherwise noted. N-Bromosuccinimideand 4-butylphenylboronic acid were recrystallized from hot water priorto use. Solvents were purified via passage through packed columns asdescribed by Pangborn and coworkers (Pangborn, 1996) (THF, Et₂O, CH₃CN,CH₂Cl₂: dry neutral alumina; hexane, benzene, and toluene, dry neutralalumina and Q5 reactant; DMSO, DMF: activated molecular sieves). Waterwas double distilled. Triethylamine, diisopropylamine, diethylamine,pyridine, and 2,6-lutidine were freshly distilled under an atmosphere ofnitrogen from CaH₂. Solutions of n-butyllithium were titrated accordingto the method of Hoye and coworkers (Hoye, T. R., 2004).

The following compounds were prepared according to literature precedent:N-isopropyliminodiacetic acid (Stein, A., 1995; Dubé, C. E., 2005),(E)-3-bromostyrylboronic acid (Perner, R. J., 2005),5-bromo-2-benzofuranylboronic acid (Friedman, M. R., 2001),2-bromo-5-methoxyphenol (Albert, J. S., 2002), 4-(methoxymethoxy)benzoicacid (Lampe, J. W., 2002), (E)-(2-bromoethenyl)dibromoborane (59)(Hyuga, S., 1987), (E)-1-chloro-2-iodoethylene (62) (Negishi, E. I.,1984; Organ, M. G., 2004),(1E,3E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)buta-1,3-dienylboronicacid (83) (Uenishi, 2003), (E)-3-bromobut-2-enal (85) (Romo, 1998),(E)-2-(tributylstannyl)vinylzinc chloride (63) (Pihko, 1999), (E)-methyl10-iododec-9-enoate (Zhang, 2006), diolCH₃—CH(OH)—CH(CH₃)—CH(OH)—CH(CH₃)—CH₂—O—CH₂—C₆H₅ (Paterson, 2001), anddichloromethylpinacolboronic ester (Wuts, 1982; Raheem, 2004).

Suzuki-Miyaura cross-coupling reactions were typically performed underan atmosphere of argon in oven- or flame-dried I-Chem or Wheaton vialssealed with poly(tetrafluoroethylene)-lined plastic caps. All otherreactions were performed in oven- or flame-dried round-bottom ormodified Schlenk flasks fitted with rubber septa under a positivepressure of argon or nitrogen unless otherwise indicated. Organicsolutions were concentrated via rotary evaporation under reducedpressure. Reactions were monitored by analytical thin layerchromatography (TLC) performed using the indicated solvent on E. Mercksilica gel 60 F254 plates (0.25 mm). Compounds were visualized byexposure to a UV lamp (λ=254 nm), a glass chamber containing iodine,and/or a solution of KMnO₄, an acidic solution of p-anisaldehyde, or asolution of ceric ammonium molybdate (CAM) followed by brief heatingusing a Varitemp heat gun. Flash column chromatography was performed asdescribed by Still and coworkers (Still, W. C., 1978) using EM Mercksilica gel 60 (230-400 mesh).

¹H NMR spectra were recorded at 23° C. on one of the followinginstruments: Varian Unity 400, Varian Unity 500, Varian Unity Inova500NB. Chemical shifts (δ) are reported in parts per million (ppm)downfield from tetramethylsilane and referenced to residual protium inthe NMR solvent (CHCl₃, δ=7.26; CD₂HCN, δ=1.93, center line) or to addedtetramethylsilane (δ=0.00). Data are reported as follows: chemicalshift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,sept=septet, m=multiplet, b=broad, app=apparent), coupling constant (J)in Hertz (Hz), and integration.

¹³C NMR spectra were recorded at 23° C. on one of the followinginstruments: Varian Unity 500 or Varian Unity Inova 500NB. Chemicalshifts (δ) are reported in ppm downfield from tetramethylsilane andreferenced to carbon resonances in the NMR solvent (CDCl₃, δ=77.0,center line; CD₃CN, δ=1.30, center line) or to added tetramethylsilane(δ=0.00). Carbons bearing boron substituents were not observed(quadrupolar relaxation).

¹¹B NMR were recorded using a General Electric GN300WB instrument andreferenced to an external standard of (BF₃.Et₂O). High resolution massspectra (HRMS) were performed by Furong Sun and Dr. Steve Mullen at theUniversity of Illinois School of Chemical Sciences Mass SpectrometryLaboratory. Infrared spectra were collected from a thin film on NaClplates on a Mattson Galaxy Series FTIR 5000 spectrometer with internalreferencing. Absorption maxima (ν_(max)) are reported in wavenumbers(cm⁻¹). X-ray crystallographic analysis was carried out by Dr. ScottWilson at the University of Illinois George L. Clark X-Ray facility.

Example 1 Preparation of Protected Organoboronic Acids Having TrivalentGroups

To form protected organoboronic acid 3 a, a 500 mL flask was chargedwith p-tolylboronic acid (3.00 g, 22.1 mmol, 1 equiv.),N-methyliminodiacetic acid (3.25 g, 22.1 mmol, 1 equiv.), benzene (360mL) and DMSO (40 mL). The flask was fitted with a Dean-Stark trap and areflux condenser, and the mixture was refluxed with stirring for 16 hfollowed by concentration in vacuo. The resulting crude product wasadsorbed onto Florisil gel from a MeCN solution. The resulting powderwas dry-loaded on top of a silica gel column slurry-packed with EtOAc.The product was eluted using a gradient (EtOAc→EtOAc:MeCN 2:1) to yieldboronate ester 3 a as a colorless, crystalline solid (5.05 g, 93%). Anx-ray structure of 3 a is shown in FIG. 3.

To form protected organoboronic acid. 3 c, a 250 mL roundbottom flaskwas charged with p-tolylboronic acid (7.36 mmol, 1.00 g),N-isopropyliminodiacetic acid (7.36 mmol, 1.29 g), benzene (150 mL) andDMSO (15 mL). The flask was fitted with a Dean-Stark trap and a refluxcondenser, and the mixture was refluxed with stirring for 14 h and thenconcentrated in vacuo. Purification by flash chromatography(Et₂O→Et₂O:MeCN 1:2) yielded boronate ester 3 c as a colorless,crystalline solid (747 mg, 37%).

To form protected organoboronic acid 3 d, a 100 mL roundbottom flask wascharged with p-tolylboronic acid (3.68 mmol, 500 mg),N-methyldiethanolamine (3.68 mmol, 422 μL) and toluene (70 mL). Theflask was fitted with a Dean-Stark trap and a reflux condenser, and thesolution was refluxed with stirring for 8 h and then allowed to cool to23° C. CaCl₂ (app. 200 mg, a fine powder) and NaHCO₃ (app. 200 mg) werethen added, and the resulting mixture was stirred for 15 min. and thenwas filtered. The filtrate was concentrated in vacuo and residualsolvent was removed via co-evaporation with CH₂Cl₂ to yield boronateester 3 d as a colorless, crystalline solid (399 mg, 50%).

Example 2 Reactivity Studies of Unprotected Organoboronic Acids andProtected Organoboronic Acids Having Trivalent Groups

The reactivity studies of the compounds of Example 1 were carried out asfollows. In a glove box, to a vial equipped with a small stir bar andcontaining the 2-(di-tert-butylphosphino)biphenyl ligand was added a0.02 M solution of Pd(OAc)₂ in THF in a volume sufficient to yield a0.04 M solution with respect to the phosphine ligand. The vial wassealed with a PTFE-lined cap, removed from the glove box, and maintainedat 65° C. with stirring for 30 min to provide the catalyst stocksolution.

In a glove box, a glass vial equipped with a small stir bar was chargedwith boronate ester 3 (0.06 mmol) and anhydrous K₃PO₄ as a finely groundpowder (32 mg, 0.15 mmol). To this vial was then added a 250 μL of a THFsolution of 4-butylphenylboronic acid (0.24 M, 0.06 mmol),4-bromobenzaldehyde (0.20 M, 0.05 mmol) and biphenyl (0.08 M, internalstd. for HPLC analysis). Finally, to this same vial was added 50 μL ofthe catalyst stock solution described above. The vial was then sealedwith a PTFE-lined cap, removed from the glove box, and maintained in a65° C. oil bath with stirring for 12 h. The reaction solution was thenallowed to cool to 23° C. and filtered through a plug of silica gel,eluting with MeCN:THF 1:1. The filtrate was then analyzed by HPLC. For

The ratio of products 5 and 6 was determined using an HPLC system(Agilent Technologies) fitted with a Waters SunFire Prep C₁₈ 5 μm column(10×250 mm, Lot No. 156-160331) with a flow rate of 4 mL/min and agradient of MeCN:H₂O 5:95→95:5 over 23 min., with UV detection at 268 nm(4-bromobenzaldehyde, t_(R)=14.66 min.; biphenyl, t_(R)=21.80 min.) and293 nm (5, t_(R)=25.79 min.; 6, t_(R)=20.50 min.; it was determined thatthe absorption coefficients for 5 and 6 at 293 nm were identical withinthe limits of experimental error).

The reaction and characterization were carried out for protectedorganoboronic acids 3 a, 3 b, 3 c and 3 d. For each species, thestarting concentration of the protected organoboronic acid was 0.06mmol. The reaction was carried out 3 times, and the product ratios wereaveraged. The reaction of 3 a yielded a 24:1.0 ratio of 5:6. Thereaction of 3 b yielded a 1.0:1.0 ratio of 5:6. The reaction of 3 cyielded a 26:1.0 ratio of 5:6. The reaction of 3 d yielded a 1.0:1.0ratio of 5:6. These results are listed in FIG. 4.

Example 3 Preparation of Halogen-Functionalized Protected OrganoboronicAcids

The general method for synthesizing protected haloorganoboronic acidswas as follows. A roundbottom flask equipped with a stir bar was chargedwith haloboronic acid (1 equiv.), N-methyliminodiacetic acid (1-1.5equiv.), and benzene:DMSO (10:1). The flask was fitted with a Dean-Starktrap and a reflux condenser, and the mixture was refluxed with stirringfor 12-18 hours. The reaction solution was allowed to cool to 23° C. andthe solvent was removed in vacuo. The resulting crude solid was absorbedonto Florisil gel from a MeCN solution. The resulting powder wasdry-loaded on top of a silica gel column slurry-packed with Et₂O. Thecolumn was flushed with a copious volume of Et₂O; the product was theneluted with a mixture of Et₂O:MeCN. All products thus obtained wereanalytically pure, colorless, crystalline solids that were indefinitelybench stable at 23° C. under air. Yields are given below and in FIG. 5.

For protected haloorganoboronic acid 8 a, the general procedure wasfollowed using 4-bromophenylboronic acid (1.00 g, 4.98 mmol, 1 equiv.),N-methyliminodiacetic acid (733 mg, 4.98 mmol), benzene (150 mL) andDMSO (15 mL). The mixture was refluxed for 12 h. The product was elutedusing a gradient; Et₂O→Et₂O:CH₃CN 1:1. Compound 8 a was isolated as ananalytically pure, colorless, crystalline solid (1.53 g, 98%).

For protected haloorganoboronic acid 8 b, the general procedure wasfollowed using 3-bromophenylboronic acid (2.00 g, 9.96 mmol),N-methyliminodiacetic acid (1.47 g, 9.96 mmol), benzene (300 mL) andDMSO (30 mL). The mixture was refluxed for 18 h. The product was elutedwith Et₂O:CH₃CN 1:1. Compound 8 b was isolated as an analytically pure,colorless, crystalline solid (2.89 g, 93%).

For protected haloorganoboronic acid 8 c, the general procedure wasfollowed using 2-bromophenylboronic acid (2.00 g, 9.96 mmol),N-methyliminodiacetic acid (1.47 g, 9.96 mmol), benzene (300 mL) andDMSO (30 mL). The mixture was refluxed for 13 h. The product was elutedwith Et₂O:MeCN 1:1. Compound 8 c was isolated as an analytically pure,colorless, crystalline solid (3.01 g, 97%).

For protected haloorganoboronic acid 8 d, the general procedure wasfollowed using 4-bromothiophene-2-boronic acid (281 mg, 1.36 mmol),N-methyliminodiacetic acid (240 mg, 1.63 mmol), benzene (50 mL) and DMSO(5 mL). The mixture was refluxed for 13 h. The product was eluted withEt₂O:MeCN 3:1. Compound 8 d was isolated as an analytically pure,colorless, crystalline solid (429 mg, 99%).

For protected haloorganoboronic acid 8 e, the general procedure wasfollowed using 2-(3-bromophenyl)ethenylboronic acid (227 mg, 1.0 mmol),N-methyliminodiacetic acid (147 mg, 1.0 mmol), benzene (50 mL) and DMSO(5 mL). The mixture was refluxed for 11 h. The product was eluted withEt₂O:MeCN 5:1. Compound 8 e was isolated as an analytically pure,colorless, crystalline solid (334 mg, 99%).

For protected haloorganoboronic acid 8 f, the initial unprotectedboronic acid, 2-(3-bromophenyl)cyclopropylboronic acid, was formed fromcompound 8 e. To a stirred solution of 8 e (1.21 g, 3.59 mmol) andPd(OAc)₂ (0.0239 g, 0.11 mmol) in THF (24 mL) at 0° C. in a 250 mLSchlenk flask was added a freshly prepared ethereal solution ofdiazomethane (35 mL of a 0.25 M solution, 8.8 mmol) dropwise over 20minutes. Additional Pd(OAc)₂ was then added (0.0239 g, 0.11 mmol) as asolution in THF (1 mL) followed by the dropwise addition over 20 min ofan additional 35 mL of 0.25 M ethereal diazomethane (8.8 mmol). Thereaction was then allowed to warm to 23° C. and the excess diazomethanewas removed under a stream of N₂. The crude reaction mixture was thenpoured into 120 mL of 0.5 M pH 7 sodium phosphate buffer and extractedwith THF:Et₂O 1:1 (3×120 mL). The combined organic fractions were thenwashed with brine, dried over Na₂SO₄, and concentrated in vacuo.Purification by flash chromatography (SiO₂, Et₂O→Et₂O:CH₃CN 1:1) yielded8 f (1.21 g, 96%). To a stirred solution of 8 f (0.513 g, 1.46 mmol) inTHF (20 mL) was added 1M aq. NaOH (4.37 mL, 4.37 mmol) and the resultingmixture was stirred at 23° C. for 20 minutes. The reaction was thenquenched with the addition of 0.5 M pH 7 phosphate buffer (20 mL) anddiluted with Et₂O (20 mL). The layers were separated and the aqueouslayer was extracted with THF:Et₂O 1:1 (40 mL). The combined organicfractions were dried over MgSO₄ and concentrated in vacuo to yield thedesired 2-(3-bromophenyl)cyclopropylboronic acid as a colorless solid(0.339 g, 97%).

Although 8 f was formed as an intermediate to2-(3-bromophenyl)cyclopropylboronic acid, the compound could also beformed by reaction of 2-(3-bromophenyl)cyclopropylboronic acid withN-methyliminodiacetic acid. In this case, the general procedure wasfollowed using 2-(3-bromophenyl)cyclopropylboronic acid (316 mg, 1.31mmol), N-methyliminodiacetic acid (232 mg, 1.58 mmol), benzene (50 mL)and DMSO (5 mL). The mixture was refluxed for 6 h. The product waseluted with MeCN:Et₂O 5:1. Compound 8 f was isolated as an analyticallypure, colorless solid (408 mg, 88%).

Example 4 Reaction of Protected Organoboronic Acids Containing HalogenGroups in the Suzuki-Miyaura Reaction

The reactivity studies of the compounds of Example 3 were carried out asfollows. In a glove box, to a vial equipped with a stir bar was addedthe phosphine ligand. To the vial was then added a 0.02 M solution ofPd(OAc)₂ in THF in a volume sufficient to yield a 0.04 M solution withrespect to the phosphine ligand. The vial was sealed with a PTFE-linedcap, removed from the glove box, and maintained at 65° C. with stirringfor 30 min to provide the catalyst stock solution.

To a 40 mL vial equipped with a stir bar was added the haloboronateester of Example 3 (1.0 mmol) and the boronic acid (typically 1.2-1.5mmol). The vial was brought into the glove box. To the vial was addedK₃PO₄ (3.0 mmol, 636.8 mg, a finely ground powder), THF (9.0 mL), andthen the catalyst stock solution (1.0 mL). The vial was capped with aPTFE-lined cap, removed from the glove box, and placed in a 65° C. oilbath with stirring for 12 h. The reaction mixture was allowed to cool to23° C. and then filtered through a very thin pad of silica gel toppedwith sand and then celite, eluting with a copious volume of MeCN. To theresulting solution was added Florisil gel (app. 25 mg/mL of solution),and then solvent was removed in vacuo. The resulting powder wasdry-loaded on top of a silica gel column slurry-packed with Et₂O. Thecolumn was flushed with a copious volume of Et₂O; the product was theneluted with Et₂O:MeCN. Reaction yields are listed in FIG. 6.

For protected organoboronic acid 9 a, the general procedure was followedusing 8 a (312 mg, 1.00 mmol), tolylboronic acid (163 mg, 1.20 mmol),and 2-(dicyclohexylphosphino)biphenyl. The product was eluted withEt₂O:MeCN 1:1. Compound 9 a was isolated as a colorless solid (280 mg,87%). This same reaction was also set up using standard Schlenktechniques without the use of a glove box. A flame-dried 25 mL Schlenkflask equipped with a stir bar was evacuated and purged with argon 3times. This flask was charged with 2-(dicyclohexylphosphino)biphenyl(14.1 mg, 0.04 mmol) Pd(OAc)₂ (4.4 mg, 0.02 mmol), and THF (10 mL). Theflask was then fitted with a reflux condenser and the yellow solutionwas heated to reflux for 5 minutes resulting in discoloration. Aseparate flame-dried 25 mL Schlenk flask equipped with a stir bar wasevacuated and purged with argon 3 times. This flask was charged withhaloboronate ester 8 a (312.1 mg, 1.00 mmol), tolylboronic acid (163.2mg, 1.20 mmol), and freshly ground anhydrous K₃PO₄ (637.2 mg, 3.00mmol). This flask was then fitted with a reflux condenser. The catalystsolution was then transferred via cannula into the flask containing thecoupling partners and base. The resulting mixture was heated at refluxfor 12 hours. The reaction was worked-up as described in the generalprocedure above. The product was eluted with Et₂O:MeCN 3:1→1:1. Compound9 a was isolated as a nearly colorless solid (279.6 mg, 87%).

For protected organoboronic acid 9 b, the general procedure was followedusing 8 b (312 mg, 1.00 mmol), tolylboronic acid (163 mg, 1.20 mmol),and 2-(dicyclohexylphosphino)biphenyl. The product was eluted withEt₂O:MeCN 1:1. Compound 9 b was isolated as a colorless, crystallinesolid (276 mg, 85%).

For protected organoboronic acid 9 c, the general procedure was followedusing 8 c (312 mg, 1.00 mmol), tolylboronic acid (172 mg, 2.00 mmol) and2-(dicyclohexylphosphino)biphenyl. The product was eluted with agradient of Et₂O:MeCN 5:1→1:1. Compound 9 c was isolated as a paleyellow solid (257 m 80%).

For protected organoboronic acid 9 d, the general procedure was followedusing 8 d (318 mg, 1.00 mmol), tolylboronic acid (204 mg, 1.50 mmol),K₂CO₃ (415 mg, 3.00 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl. Theproduct was eluted using a gradient of Et₂O:MeCN 5:1→3:1. Compound 9 dwas isolated as a pale yellow solid (266 mg, 81%).

For protected organoboronic acid 9 e, the general procedure was followedusing 8 e (338 mg, 1.00 mmol), tolylboronic acid (163 mg, 1.20 mmol),and 2-(dicyclohexylphosphino)biphenyl. The product was eluted withEt₂O:MeCN 5:1. Compound 9 e was isolated as an off-white solid (282 mg,82%).

For protected organoboronic acid 9 f, the general procedure was followedusing 8 f (237 mg, 0.674 mmol), tolylboronic acid (109 mg, 0.808 mmol),K₃PO₄ (429 mg, 2.02 mmol), catalyst stock solution containing2-(dicyclohexylphosphino) biphenyl (674 μL), and THF 6.06 mL. Theproduct was eluted with Et₂O:MeCN (1:1). Compound 9 f was isolated as anoff-white crystalline solid (229 mg, 94%).

Example 5 Deprotection of Protected Organoboronic Acids

The general method for deprotecting the protected organoboronic acids ofExample 4 was as follows. A round bottom flask equipped with a stir barwas charged with the boronate ester (1 equiv.), THF (10 mL), and 1M aq.NaOH (3 equiv.) and the resulting mixture was vigorously stirred at 23°C. for 10 minutes. The reaction mixture was then diluted with aq. sodiumphosphate buffer (0.5 M, pH 7.0, mL) and Et₂O (10 mL), the layers wereseparated, and the aq. phase was extracted once with THF:Et₂O 1:1 (20mL). (On some occasions phosphate salts precipitated and during theextraction process and were redissolved by the addition of water. Thecombined organic fractions were then dried over MgSO₄ and concentratedin vacuo. Residual solvent was co-evaporated with MeCN. Reaction yieldsare listed in FIG. 6

For organoboronic acid 10 a, the general procedure was followed using 9a (261 mg, 0.806 mmol) and 1 M aq. NaOH (2.42 mL, 2.42 mmol). Compound10 a was isolated as a white solid (147.4 mg, 86%).

For organoboronic acid 10 b, the general procedure was followed using 9b (268 mg, 0.830 mmol) and 1 M aq. NaOH (2.49 mL, 2.49 mmol). Compound10 b was isolated as a white solid (161 mg, 92%).

For organoboronic acid 10 c, the general procedure was followed using 9c (236 mg, 0.729 mmol) and 1M aq. NaOH (2.19 mL, 2.19 mmol). Compound 10c was isolated as a white solid (150 mg, 97%). In another approach,hydrolysis was performed with NaHCO₃ instead of NaOH. This deprotectionwas carried out as follows. To a 40 mL I-Chem vial equipped with a stirbar and containing 8 c (0.672 mmol, 217 mg) was added MeOH (7 mL) andsat. aq. NaHCO₃ (3.5 mL). The mixture was vigorously stirred for 6 h at23° C. The mixture was then diluted with saturated aq. NH₄Cl (7 mL) andEt₂O (14 mL), and the phases were separated. The aqueous phase was twiceextracted with Et₂O (14 mL), and the combined organics were dried overMgSO₄ and concentrated in vacuo. The residue was twice suspended in MeCNfollowed by concentration in vacuo and then dissolved in CH₂Cl₂ andconcentrated in vacuo to yield 10 c as a colorless, crystalline solid(121 mg, 85%).

For organoboronic acid 10 d, the general procedure was followed using 9d (226 mg, 0.686 mmol) and 1 M aq. NaOH (2.06 mL, 2.06 mmol). Compound10 d was isolated as a pale green solid (131 mg, 88%).

For organoboronic acid 10 e, the general procedure was followed using 9e (243 mg, 0.696 mmol) and 1 M aq. NaOH (2.09 mL, 2.09 mmol). Compound10 e was isolated as an off-white solid (138 mg, 83%).

For organoboronic acid 10 f, the general procedure was followed using 9f (202 mg, 0.56 mmol) and 1M aq. NaOH (1.67 mL, 1.67 mmol). Compound 10f was isolated as an off-white solid (127 mg, 91%).

Example 6 Preparation of Protected Organoboronic Acid for Use in TotalSynthesis of Ratanhine

Protected haloorganoboronic acid 13 was synthesized by the generalprocedure of Example 3, using 5-bromo-2-benzofuranylboronic acid(Friedman, M. R., 2001) (1.33 g, 5.50 mmol), N-methyliminodiacetic acid(970 mg, 6.60 mmol), benzene (80 mL) and DMSO (8 mL). The mixture wasrefluxed for 13 h. The product was eluted using a gradient of Et₂O:MeCN1:1→1:2. Compound 13 was isolated as an analytically pure, off-white,crystalline solid (1.73 g, 90%).

Example 7 Preparation of Protected Organoboronic Acid for Use in TotalSynthesis of Ratanhine

Protected haloorganoboronic acid 14 was synthesized by a multi-stepprocess. To a stirred mixture of 2-bromo-5-methoxyphenol (Albert, 2002)(2.19 g, 10.8 mmol) and K₂CO₃ (4.46 g, 32.3 mmol) in acetone (55 mL) wasadded chloromethyl methyl ether (1.63 mL, 21.5 mmol). The mixture wasrefluxed for 3 h and then allowed to cool to 23° C. The mixture wasfiltered and the filtrate was concentrated in vacuo. The crude productwas then purified by flash chromatography (SiO₂, hexanes:EtOAc 95:5) toprovide 2-bromo-5-methoxy-1-methoxymethoxybenzene as a colorless liquid(2.43 g, 92%).

To a stirred solution of 2-bromo-5-methoxy-1-methoxymethoxybenzene (1.04g, 4.23 mmol) in THF (13 mL) at −95° C. (hexanes/N₂) was added n-BuLi(1.6 M in hexanes, 2.91 mL, 4.65 mmol) and the resulting solution wasstirred for 5 min. To this solution was then added by syringe a solutionof I₂ (1.28 g, 5.07 mmol) in THF (8.5 mL) until a yellow colorpersisted. The solution was then permitted to warm to 23° C. andconcentrated in vacuo. The residue was purified by flash chromatography(SiO₂, petroleum ether:Et₂O 8:1) to provide2-iodo-5-methoxy-1-methoxymethoxybenzene as a pale-orange oil (1.04 g,84%). See also Tsukayama, M., 1997.

To a stirred solution of 2-iodo-5-methoxy-1-methoxymethoxybenzene (5.24g, 17.8 mmol) in MeCN (55 mL) was added silica gel (1.32 g),2,6-di-tert-butyl-4-hydroxytoluene (60 mg), and then N-bromosuccinimide(3.17 g, 17.8 mmol). The mixture was stirred at 23° C. for 1 hour andthen filtered. The filtrate was concentrated in vacuo and the residuewas dissolved in CH₂Cl₂ (100 mL). To this solution was added water (100mL) and the resulting mixture was vigorously stirred for 5 min. Thelayers were then separated and the aq. phase was extracted with CH₂Cl₂(2×100 mL). The combined organics were dried over MgSO₄ and concentratedin vacuo. The residue was purified by flash-column chromatography (SiO₂,petroleum ether:Et₂O 8:1) to provide2-iodo-4-bromo-5-methoxy-1-methoxymethoxybenzene as a yellow oil (5.05g, 76%).

In a glove box, to a 40 mL I-Chem vial equipped with a stir bar andcontaining 2-iodo-4-bromo-5-methoxy-1-methoxymethoxybenzene (500 mg,1.34 mmol) was added potassium acetate (395 mg, 4.02 mmol),bis(neopentylglycolato)diboron (363 mg, 1.61 mmol) and PdCl₂(dppf) (33mg, 0.040 mmol). The vial was sealed with a septum cap and then removedfrom the glove box. To the vial was then added DMSO (11 mL) and theresulting mixture was sealed under an atmosphere of argon and stirred at80° C. for 13 h. The mixture was then allowed to cool to 23° C. and 1 Maq. NaOH was added (0.9 mL, 0.9 mmol). The mixture was stirred at 23° C.for 10 minutes and then diluted with saturated aq. NH₄Cl (50 mL), water(50 mL), and Et₂O (100 mL). The layers were separated and the organicphase was washed with water (3×100 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was thrice dissolved in MeCN andconcentrated in vacuo to afford a crude sample of2-methoxymethoxy-4-methoxy-5-bromophenyl boronic acid as a light brownsolid (343 mg): TLC (EtOAc) R_(f)=0.50, stained by KMnO₄; ¹H-NMR (400MHz, CDCl₃) δ 7.97 (s, 1H), 6.75 (s, 1H), 5.97 (s, 2H), 5.29 (s, 2H),3.91 (s, 3H), 3.52 (s, 3H). To this crude boronic acid dissolved inbenzene:DMSO (10:1) was added N-methyliminodiacetic acid (210 mg, 1.43mmol). The flask was fitted with a Dean-Stark trap and a refluxcondenser and the mixture was refluxed with stirring for 11 h followedby concentration in vacuo. The resulting crude product was adsorbed ontoFlorisil gel from a MeCN solution. The resulting powder was dry-loadedon top of a silica gel column slurry-packed with Et₂O. The column wasflushed with a copious volume of Et₂O and then the product was elutedwith Et₂O:MeCN 1:1 to yield building block 14 as an off-white solid (365mg, 68% yield over two steps).

Example 8 Preparation of Haloorganic Compound for Use in Total Synthesisof Ratanhine

Haloorganic compound 15 was synthesized by a multi-step process. To amixture of methyltriphenylphosphonium bromide (14.08 g, 39.4 mmol) intoluene at 23° C. was added a solution of potassium tert-butoxide (4.47g, 39.8 mmol) in THF (60 mL) dropwise via cannula, and the resultingmixture was allowed to stir at 23° C. for 4 hours. The resulting yellowmixture was cooled to −78° C. and a solution of 4-iodo-salicylaldehyde(4.35 g, 17.5 mmol) in toluene (40 mL) was added dropwise via cannula.The resulting mixture was allowed to slowly warm to 23° C. and wasstirred at that temperature for 12 hours. The reaction was then quenchedwith the addition of saturated aq. ammonium chloride (100 mL). Theresulting mixture was then diluted with water (200 mL) and extractedwith Et₂O (3×100 mL). The combined organic fractions were then washedwith brine (100 mL), dried over magnesium sulfate, and concentrated invacuo. Purification by flash chromatography (SiO₂, hexanes:ethyl acetate7:1→1:1) yielded 2-hydroxy-5-iodostyrene as a colorless solid (4.0 g,98%). See also Gligorich, K. M., 2006.

To a stirred solution of 2-hydroxy-5-iodostyrene,4-(methoxymethoxy)benzoic acid, and DCC in methylene chloride at 23° C.was added DMAP, and the resulting mixture was stirred at 23° C. for 21hours. The reaction mixture was then filtered over celite andconcentrated in vacuo. Purification by flash chromatography (SiO₂,hexanes:ethyl acetate 5:1) yielded(2-vinyl-4-iodophenyl)-4-methoxymethoxybenzoate as a colorless solid(4.6 g, 79%).

To a stirred solution of (2-vinyl-4-iodophenyl)-4-methoxymethoxybenzoate(azeotropically dried with 2×50 mL benzene) in methylene chloride at 0°C. was added bromine dropwise via syringe over 5 minutes. The resultingsolution was stirred at 0° C. for an additional 5 minutes and thenconcentrated in vacuo at 0° C. over 30 min. Residual bromine was removedvia co-evaporation with 3×15 mL of methylene chloride at 0° C. Theresulting crude product mixture was then purified by flashchromatography (SiO₂, hexanes:ethyl acetate 5:1→2:1) to yield(2-(1,2-dibromoethyl)-4-iodophenyl)-4-methoxymethoxybenzoate as acolorless solid (3.7 g, 59%).

To a stirred solution of(2-(1,2-dibromoethyl)-4-iodophenyl)-4-methoxymethoxybenzoate (3.61 g,6.33 mmol, azeotropically dried with acetonitrile) in acetonitrile (75mL) at 23° C. was added DBU (1.928 g, 12:7 mmol, 2.0 eq.) dropwise viasyringe over 2 minutes. The resulting mixture was stirred at 23° C. for25 min. The reaction was then quenched with the addition of 1 M aq. HCl(200 mL) and the resulting mixture was extracted with ethyl acetate(1×200 mL and 2×125 mL). The combined organic fractions were washed withbrine (100 mL), dried over magnesium sulfate, and concentrated in vacuo.Flash chromatography (SiO₂, petroleum ether:Et₂O 3:1) yielded(2-(1-bromoethenyl)-4-iodophenyl)-4-methoxymethoxybenzoate as acolorless oil (3.01 g, 97%).

In a glove box, to a 40 mL I-Chem vial equipped with a stir bar andcontaining (2-(1-bromoethenyl)-4-iodophenyl)-4-methoxymethoxybenzoate(0.8695 g, 1.78 mmol; azeotropically-dried with 3×5 mL benzene) wasadded K₃PO₄ (0.7548 g, 3.56 mmol), propenylboronic acid (0.183 g, 2.13mmol) as a solution in THF (3.6 mL), and PdCl₂dppf (72.6 mg, 0.09 mmol)as a solid. An additional 6.8 mL of THF was added and the resultingmixture was sealed with a PTFE-lined cap and maintained at 65° C. withstirring for 15 hours. The reaction mixture was then allowed to cool to23° C., quenched with the addition of 1 M pH 7 phosphate buffer (60 mL),and extracted with diethyl ether (3×60 mL). The combined organicfractions were then washed with water (20 mL) and brine (40 mL), driedover MgSO₄, and concentrated in vacuo. Flash chromatography (SiO₂,toluene) yielded haloorganic compound 15 as a colorless oil (0.4994 g,1.24 mmol, 70%).

Example 9 Total Synthesis of Ratanhine Using Iterative Suzuki-MiyauraReactions

Suzuki-Miyaura coupling reactions were performed with 15 and withprotected haloorganoboronic acids 13 and 14, using the general procedureof Example 4. The reaction scheme and yields are given in FIG. 10. Inthe first step, the reactants were 13 (352 mg, 1.00 mmol) and(E)-1-propenylboronic acid (144 mg, 2.00 mmol). The product was elutedusing a gradient of Et₂O:MeCN 10:1→1:1. The desired product 16 wasisolated as a colorless crystalline solid (251 mg, 80%).

The general procedure for deprotection of boronate esters of Example 5was followed using 16 (313 mg, 1.00 mmol), and 1 M aq. NaOH (3.0 mL, 3.0mmol) to afford the free boronic acid as an off-white solid (188 mg,93%); TLC: (EtOAc) R_(f)=0.2, visualized by UV; HRMS (EI+): Calculatedfor C₁₁H₁₁O₃B (M)⁺ 202.0801. Found 202.0805. The free boronic acid wasfound to be very sensitive to decomposition upon storage and wastherefore used immediately in the next reaction. In a glove box, to a 40mL I-Chem vial containing 14 (141 mg, 0.351 mmol) was added the freeboronic acid (106 mg, 0.526 mmol) as a solution in THF (3.15 mL)followed by solid K₂O₃ (145 mg, 1.05 mmol). To the vial was then added350 μL of a THF catalyst stock solution containing2-(dicyclohexylphosphino) biphenyl (0.04 M) and Pd₂ dba₃ (0.01 M), whichwas preincubated at 65° C. for 30 min. with stirring. The vial wassealed with a PTFE-lined cap, removed from the glove box, and maintainedat 80° C. with stirring for 28 h. The reaction mixture was allowed tocool to 23° C., and was then passed through a thin pad of silica geltopped with Celite, eluting with a copious volume of Et₂O. The filtratewas concentrated in vacuo and the resulting crude product was adsorbedonto Florisil gel from a MeCN solution. The resulting powder wasdry-loaded on top of a silica gel column slurry-packed with Et₂O. Thecolumn was flushed with a copious volume of Et₂O; the product was theneluted with Et₂O:MeCN 3:1 to yield protected organoboronic acid 17 as anoff-white solid (123 mg, 73%).

A 6 mL vial equipped with a stir bar was charged with protectedorganoboronic acid 17 (51 mg, 0.106 mmol), THF (1.0 mL), and 1 M aq.NaOH (0.32 mL, 0.32 mmol). The resulting mixture was vigorously stirredfor 10 min., then diluted with 0.5 M pH 7 phosphate buffer (2.0 mL) andEt₂O (1.0 mL). The phases were separated and the aqueous phase wasextracted once with THF:Et₂O 1:1 (2.0 mL). The combined organics weredried over MgSO₄, filtered, and then concentrated in vacuo. Residualsolvent was removed via coevaporation with PhMe, followed by MeCN (2×),and then CH₂Cl₂ (2×) (bath temperature maintained at <30° C.) to yieldthe free boronic acid as an off-white solid (39.2 mg, 99%): TLC (EtOAc)R_(f)=0.53, visualized by UV; ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H),7.49 (s, 1H), 7.42 (d, J=8 Hz, 1H), 7.26 (m, 1H), 7.17 (s, 1H), 6.84 (s,1H), 6.49 (d, J=16 Hz, 1H), 6.20 (dq, J=16, 6.4 Hz, 1H), 5.77 (s, 2H),5.35 (s, 2H), 4.03 (s, 3H), 3.55 (s, 3H), 1.90 (d, J=6.4 Hz, 3H); HRMS(TOF ES+): Calculated for C₂₀H₂₂O₆B (M+H)⁺ 369.1509, Found 369.1515.

This free boronic acid was then quantitatively transferred as a solutionin THF to a 6 mL vial containing 15 (28.5 mg, 0.071 mmol), and thesolvent was removed in vacuo. In the glove box, to this vial was addedsolid K₂CO₃ (39.2 mg, 0.28 mmol), and a freshly-prepared THF solution(1.06 mL) of 2-(dicyclohexylphosphino)biphenyl (0.008 M) and Pd₂ dba₃(0.002 M). A stir bar was added and the vial was sealed with aPTFE-lined cap, removed from the glove box, and maintained at 65° C.with stirring for 20 h. The reaction mixture was then allowed to cool to23° C. and passed through a thin pad of silica gel topped with Celite,eluting with a copious volume of EtOAc. The filtrate was concentrated invacuo, and the resulting crude product was adsorbed onto Florisil gelfrom a CH₂Cl₂ solution. The resulting powder was dry-loaded on top of asilica gel column slurry-packed with hexanes:EtOAc 10:1. The column waseluted with hexanes:EtOAc 10:1→3:1 to yield protected ratanhine 18 as aviscous yellow oil (37.0 mg, 81%).

In an unoptimized procedure, a 6 mL vial equipped with a stir bar wascharged with 18 (27 mg, 0.042 mmol), THF (0.3 mL), MeOH (0.6 mL), andconcentrated HCl (12 μL). The vial was sealed with a PTFE-lined cap andmaintained at 65° C. with stirring for 1 h. The solution was thenallowed to cool to 23° C. and diluted with H₂O (1 mL), THF (1 mL) andEt₂O (2 mL). The phases were separated and the aq. phase was extractedrepeatedly with EtOAc. The combined organics were concentrated in vacuoand the resulting crude product was purified by preparative HPLC (WatersSunFire Prep C₁₈ OBD 30×150 mm column, Lot #168I161701, 25 mL/min.,H₂O:MeCN 95:5→5:95 over 20 min., then H₂O:MeCN 5:95 for 15 min.;t_(R)=24.84 min with UV detection at 325 and 218 nm) to yield 11 (9.6mg, 41%) [¹H NMR analysis demonstrated that this sample contained asmall amount (˜5-10%) of an unidentified impurity.] An optimizedpreparative HPLC method was subsequently developed (Waters SunFire PrepO₁₈ OBD 30×150 mm column, Lot #168I161701, 33 mL/min., isochraticH₂O:MeCN 20:80; t_(R)=21.72 min with UV detection at 325 and 218 nm)that yielded the pure natural product. ¹H NMR, ¹³C NMR, HRMS, and IRanalysis of synthetic 11 were fully consistent with the data reportedfor the isolated natural product ratanhine, thus confirming the originalstructure proposed by Arnone and coworkers (Arnone, 1990).

Example 10 Determination of Conformational Rigidity of Protecting Groups

Conformational rigidity of the organic protecting groups of compounds 19and 193 were determined by the “conformational rigidity test”. A sampleof 193 (approximately 10 mg) was dissolved in dry d₆-DMSO and wastransferred to a 5 mm NMR tube. The sample was analyzed on a VarianUnity 500 MHz NMR spectrometer. First, a ¹H-NMR was obtained at 23° C.The sample temperature was then increased incrementally to 30° C., 35°C., 40° C., 45° C., 50° C., 55° C., 60° C. and 70° C. At eachtemperature the sample shim was optimized, and a ¹H-NMR spectrum wasobtained. Upon cooling to 23° C., a ¹H-NMR spectrum was obtained whichwas identical to that previously obtained at this temperature. A sampleof 19 (approximately 10 mg) was dissolved in dry d₆-DMSO and wastransferred to a 5 mm NMR tube. This sample was analyzed in the sameway, except that ¹H-NMR spectra were obtained at 23° C., 60° C., 80° C.,110° C., 150° C., and then again at 23° C.

For 193, twelve peaks in the ¹H-NMR spectrum corresponding todiastereotopic methylene protons were present from 3.833 to 3.932 at 23°C. As the temperature was raised, these peaks began to coalescence attemperatures as low as 40° C. The peaks had completely coalesced into asingle peak at 3.921 by 70° C. Thus, the protecting group of 193 was notconformationally rigid.

For 19, four peaks in the ¹H-NMR spectrum corresponding todiastereotopic methylene protons were present from 3.992 to 4.236 at 23°C. As the temperature was raised, these peaks remained split into fourdistinct peaks. No coalescence was observed, even in the spectrumobtained at 150° C. Thus, the protecting group of 19 wasconformationally rigid.

Example 11 Synthesis of Protected Haloalkenylboronic Acid 54 a

(E)-(2-bromoethenyl)dibromoborane (59) was synthesized according to aliterature procedure (Hyuga, S., 1987). A subsequent reaction with 59was conducted in a subdued light environment in an oven-dried 500 mLthree-neck round bottom flask equipped with a magnetic stir bar. To astirred mixture of N-methyliminodiacetic acid (MIDA, 1) (16.93 g, 113.9mmol, 1.50 eq.) and 2,6-lutidine (17.69 mL, 151.86 mmol, 2.0 eq.) inDMSO (250 mL) at 0° C. under nitrogen was added freshly distilled 59(21.00 g, 75.93 mmol) dropwise via syringe over 15 min. The reactionmixture was allowed to warm to 23° C. and then stirred at 23° C. for 48h. The resulting yellow mixture was treated with water (300 mL) andextracted with THF:diethyl ether 1:1 (3×500 mL). The combined organicphases were washed with brine (3×350 mL), dried over anhydrous magnesiumsulfate, and concentrated in vacuo to provide a tight yellow solid. Thecrude product was purified by flash chromatography on silica gel(EtOAc:petroleum ether 1:1→EtOAc→EtOAc:MeCN 9:1) to give 54 a as acolorless crystalline solid (11.98 g, 45.75 mmol, 60%). Crystalssuitable for X-ray crystallography analysis were grown by slowevaporation from ethyl acetate at 23° C. This material was stored underair at 23° C. for one year and six months without decomposition.

Example 12 Synthesis of Bis-Borylated Olefin, and its Use in SelectiveCross-Coupling Synthesis of (E)-(2-pinacolethenyl)boronate ester (61)

A solution of the catalyst was prepared as follows: A 20 mL Wheaton vialequipped with a magnetic stir bar was charged with PdCl₂(CH₃CN)₂ (7.9mg, 0.030 mmol, 1.0 eq.) and2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4 d) (38.0 mg,0.090 mmol, 3.0 eq.). Toluene (3.00 mL) was added and the vial wassealed with a PTFE-lined plastic cap. The resulting mixture was stirredat 23° C. for 30 min yielding a clear yellow Pd/4 d catalyst solution.

This catalyst solution was then utilized in the following procedure: A30 mL Wheaton vial equipped with a magnetic stir bar was charged with 54a (0.262 g, 1.00 mmol, 1.0 eq.), bis(pinacolato)diboron (60) (0.324 g,1.25 mmol, 1.25 eq.), potassium acetate (0.297 g, 3.00 mmol, 3.0 eq.),toluene (5.0 mL), and catalyst solution (3.0 mL, 3.0 mol % Pd). The vialwas sealed with a PTFE-lined plastic cap, and the reaction mixture wasstirred for 36 h at 45° C. The resulting heterogeneous mixture wasdiluted with ethyl acetate (5.0 mL) and filtered through short pad ofCelite. Concentration of the filtrate in vacuo provided a light yellowsolid. This crude product was purified by flash chromatography on silicagel (EtOAc:Petroleum ether 1:1→EtOAc→EtOAc:MeCN 15:1) to give(E)-(2-pinacolethenyl)boronate ester 61 as a colorless crystalline solid(0.219 g, 0.710 mmol, 71%). Crystals suitable for X-ray crystallographyanalysis were grown by slow evaporation from EtOAc at 23° C. Thismaterial was stored under air at 23° C. for one year and six monthswithout decomposition.

Synthesis of (E,E)-1,3-butadienyl-(4-chloro)boronate (54 b)

To a 20 mL I-Chem vial equipped with a stir bar was added 61 (320 mg,1.05 mmol, 1.0 eq.), finely ground anhydrous K₃PO₄ (669 mg, 3.15 mmol,3.0 eq.), PdCl₂dppf.CH₂Cl₂ (26 mg, 0.32 mmol, 3 mol %), and(E)-1-chloro-2-iodoethylene (62) (396 mg, 2.10 mmol, 2.0 eq.). The vialwas sealed with a PTFE-lined cap and DMSO (8.4 mL) was added viasyringe. The resulting mixture was stirred at 23° C. for 9 h. Thereaction was quenched with the addition of 0.5 M pH 7 phosphate buffer(8 mL) and the resulting mixture was extracted with THF:Et₂O 1:1 (4×15mL). The combined organic extracts were washed with brine (25 mL), driedover Na₂SO₄, and concentrated in vacuo. The resulting residue wasdiluted with acetone (15 mL) and concentrated onto Florisil®. Theresulting powder was dry-loaded on top of a silica gel column and flashchromatography was performed (hexanes:EtOAc 1:1→EtOAc→EtOAc:MeCN 9:1) toyield 54 b as a colorless crystalline solid (139 mg, 0.571 mmol, 54%).

Example 13 Synthesis of Bis-Metallated Olefin, and its Use in SelectiveCross-Coupling (E,E)-1,3-butadienyl-4-(tributylstannyl)boronate ester(64)

A solution of the catalyst was prepared as follows: To a 4 mL vialequipped with a magnetic stir bar and containing2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4 d) (15.2 mg,0.037 mmol, 2.0 eq.) was added a solution of Pd(OAc)₂ in THF (0.095 M,0.19 mL, 0.018 mmol, 1.0 eq.). The vial was sealed with a PTFE-lined capand maintained at 23° C. with stirring for 15 min. yielding a clearyellow Pd/4 d catalyst solution.

This catalyst solution was then utilized in the following procedure:(E)-2-(tributylstannyl)vinylzinc chloride (63) was prepared according toliterature precedent (Pihko, 1999). During the formation of the Negishireagent 63, to a slurry of 54 a (50 mg, 0.191 mmol, 1.0 eq.) in THF (0.2mL) at 23° C. was added the catalyst stock solution described above(0.10 mL, 0.0095 mmol Pd, 5 mol % Pd), and the resulting slurry wasstirred for 30 min before cooling to 0° C. Negishi reagent 63 was thencannulated into the 54 a solution over 5 min. After 2 h at 0° C. thereaction was diluted with EtOAc (10 mL) and then concentrated in vacuo.The resulting red oil was dissolved in EtOAc and filtered through ashort pad of silica gel with a copious amount of EtOAc, and the filtratewas concentrated in vacuo. The resulting crude product was purified byflash chromatography on silica gel (EtOAc:hexanes 1:1 EtOAc) to yield 64as a pale yellow foam (62.2 mg, 0.125 mmol, 66%).

(E,E,E)-(6-chloro)-1,3,5-hexatrienylboronate ester (54 c)

A 30 mL Wheaton vial equipped with a magnetic stir bar was charged withPd₂(dba)₃ (0.021 g, 0.023 mmol, 1.5 mol %), Ph₃As (0.014 g, 0.046 mmol,3.0 mol %), 64 (0.760 g, 1.53 mmol, 1.0 eq.) as a solution in DMF (5.0mL), and finally (E)-1-chloro-2-iodoethylene (0.575 g, 3.05 mmol, 2.0eq.). The vial was sealed with a PTFE-lined plastic cap, and thereaction mixture was stirred at 23° C. for 3.5 h. To the resulting deepreddish mixture was then added saturated aqueous Na₂S₂O₃ (50 mL) and theresulting mixture was extracted with EtOAc (3×85 mL). The combinedorganic extracts were washed with brine (3×50 mL), dried over anhydrousmagnesium sulfate, and concentrated in vacuo to provide an orange solid.This crude product was purified by flash chromatography on Florisil®(petroleum ether:EtOAc 1:1→EtOAc→EtOAc:MeCN 9:1) to give 54 c as a lightyellow solid (0.297 g, 1.10 mmol, 72%).

Example 14 Selective Couplings Using Protected Haloalkenylboronic Acid54 a Suzuki-Miyaura Coupling—Synthesis of (E,E)-1,3-heptadienylboronateester (68)

A solution of the catalyst was prepared as follows: An oven-driedWheaton vial equipped with a magnetic stir bar was charged with Pd(OAc)₂(5.60 mg, 0.025 mmol, 1.0 eq.) and2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4 d) (20.5 mg,0.050 mmol, 2.0 eq.). Toluene (3.00 mL) was added and the vial wassealed with a PTFE-lined plastic cap. The resulting mixture was stirredat 23° C. for 45 min. resulting in a yellow Pd/4 d catalyst solution(0.00833 N Pd in toluene).

This catalyst solution was then utilized in the following procedure: Anoven-dried Wheaton vial equipped with a magnetic stir bar was chargedwith 54 a (0.262 g, 1.00 mmol, 1.0 eq.), (E)-1-pentenylboronic acid 55(0.171 g, 1.50 mmol, 1.5 eq.), KF (0.116 g, 2.00 mmol, 2.0 eq.), toluene(7.0 mL) and the catalyst solution (1.20 mL, 0.01 mmol, 1.0 mol % Pd).The vial was then sealed with PTFE-lined plastic cap, and the reactionmixture was stirred at 23° C. for 36 h. The resulting heterogeneouslight yellow mixture was diluted with acetonitrile (10.0 mL) andfiltered through a short pad of Celite. The filtrate was concentrated invacuo. The crude product was then purified by flash chromatography onsilica gel (petroleum ether:EtOAc 1:1→EtOAc→EtOAc:MeCN 9:1) to give 68as a colorless crystalline solid (0.241 g, 0.959 mmol, 96%).

Suzuki-Miyaura Coupling—Synthesis of(E,E)-1,3-butadienyl-(4-phenyl)boronate ester (80)

A solution of the catalyst was prepared as follows: A 20 mL Wheaton vialequipped with a magnetic stir bar was charged with Pd(OAc)₂ (5.60 mg,0.025 mmol, 1.0 eq.) and2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4 d) (20.5 mg,0.050 mmol, 2.0 eq.). Toluene (3.00 mL) was added and the vial wassealed with a PTFE-lined plastic cap. The resulting mixture was stirredat 23° C. for 45 min. resulting in a yellow Pd/4 d catalyst solution(0.00833 N Pd in toluene).

This catalyst solution was then utilized in the following procedure: A30 mL Wheaton vial equipped with a magnetic stir bar was charged with 54a (0.262 g, 1.00 mmol, 1.0 eq.), trans-2-phenylvinylboronic acid (0.229g, 1.50 mmol, 1.5 eq.), KF (0.116 g, 2.00 mmol, 2.0 eq.; based on 54 a),toluene (7.0 mL), and the catalyst solution (1.20 mL, 0.01 mmol, 1.0 mol% Pd). The vial was then sealed with a PTFE-lined plastic cap, and thereaction mixture was stirred for 24 hr at 23° C. The resultingheterogeneous yellow mixture was diluted with acetonitrile (10.0 mL),filtered through short pad Celite using acetonitrile (100 mL), andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel (EtOAc:Petroleum ether 1:1→EtOAc→EtOAc:MeCN2:1) to give 80 as a colorless crystalline solid (0.263 g, 0.922 mmol,92%).

Stille Coupling—Synthesis of (E,E)-1,3-butadienyl-boronate ester (70)

A 30 mL Wheaton vial equipped with a magnetic stir bar was charged with54 a (0.262 g, 1.00 mmol, 1.0 eq.), Pd₂ dba₃ (0.037 g, 0.040 mmol, 4.0mol % Pd), Fur₃P (0.021 g, 0.090 mmol, 9.0 mol %), DMF (8.0 mL) andtributyl(vinyl)tin (69) (0.346 mL, 1.15 mmol, 1.15 eq.). The vial wasthen sealed with a PTFE-lined plastic cap, and the reaction mixture wasstirred for 12 h at 45° C. The resulting reddish mixture was dilutedwith brine (50 mL) and then extracted with ethyl acetate (3×100 mL). Thecombined organic fractions were dried over anhydrous magnesium sulfateand concentrated in vacuo. The crude product was purified by flashchromatography on silica gel (EtOAc:Petroleum ether 1:1→EtOAc→EtOAc:MeCN15:1) to give 70 as a colorless crystalline solid (0.190 g, 0.909 mmol,91%).

Heck Coupling—Synthesis of (E,E)-1,3-butadienyl-(4-methylester)boronateester (72)

A 30 mL Wheaton vial equipped with a magnetic stir bar was charged with54 a (0.262 g, 1.00 mmol, 1.0 eq.), PPh₃ (0.0159 g, 0.060 mmol, 6.0 mol%), Pd(OAc)₂ (0.0067 g, 0.030 mmol, 3.0 mol % Pd), Et₃N (0.279 mL, 2.00mmol, 2.0 eq.; based on 54 a), methyl acrylate (71) (0.136 mL, 1.50mmol, 1.5 eq.), and DMF (7.0 mL). The vial was sealed with a PTFE-linedplastic cap, and the reaction mixture was stirred at 45° C. for 12 h.The resulting mixture was diluted with brine (50 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were dried overanhydrous magnesium sulfate and concentrated in vacuo. The crude productwas purified by flash chromatography on silica gel (EtOAc:Petroleumether 1:1→EtOAc→EtOAc:MeCN 15:1) to give 72 as a light yellow solid(0.240 g, 0.898 mmol, 90%).

Sonogashira Coupling—Synthesis of (E)-2-trimethylsilylethyleneboronateester (74)

A 30 mL Wheaton vial equipped with a magnetic stir bar was charged with54 a (0.262 g, 1.00 mmol, 1.0 eq.), Pd(PPh)₄ (0.058 g, 0.050 mmol, 5.0mol %), CuI (0.019 g, 0.100 mmol, 10.0 mol %), piperidine (0.227 mL,2.30 mmol, 3.0 eq.), THF (5.0 mL), and trimethylsilylacetylene (73)(0.166 mL, 1.15 mmol, 1.5 eq.). The vial was then sealed with aPTFE-lined plastic cap, and the reaction mixture was stirred at 23° C.for 3 h. The resulting mixture was diluted with EtOAc (5.0 mL) andfiltered through a short pad of silica gel using EtOAc (100 mL). Thefiltrate was concentrated in vacuo, and the resulting crude product waspurified by flash chromatography on silica gel (EtOAc:Petroleum ether1:1→EtOAc) to give 74 as a colorless crystalline solid (0.203 g, 0.728mmol, 73%).

Example 15 Cross-Coupling Between a Trienylchloride and a VinylboronicAcid

A solution of the palladium catalyst was prepared as follows: To a 4 mLvial equipped with a stir bar and containing2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4 c) (3.0mg, 0.0063 mmol, 2.0 eq.) in THF (0.577 mL) was added a solution ofPd(OAc)₂ in THF (0.00547 M, 0.577 mL, 0.0032 mmol, 1.0 eq.). The vialwas sealed with a PTFE-lined cap and stirred at 23° C. for 15 min.

This catalyst solution was then utilized in the following procedure: Toa 7 mL vial equipped with a magnetic stir bar and containing 54 c (11.0mg, 0.0408 mmol, 1.0 eq.) was added (E)-1-penten-1-ylboronic acid (55)(7.0 mg, 0.0612 mmol, 1.5 eq.), Cs₂CO₃ (39.9 mg, 0.122 mmol, 3.0 eq.),THF (0.835 mL) and the catalyst solution (0.298 mL, 2 mol % Pd). Theresulting mixture was then sealed with a PTFE-lined plastic cap andstirred at 45° C. for 24 h. (54 c and product 75 were best separated onTLC plates by eluting twice with EtOAc). The resulting heterogeneousmixture was diluted with ethyl acetate (˜1.0 mL) and filtered through athin pad of Florisil® with copious amounts of EtOAc. The crude productwas purified by flash chromatography on Florisil® (petroleum ether:EtOAc1:1→EtOAc→EtOAc:MeCN 15:1) to give(E,E,E,E)-1,3,5,7-undecatetraenylboronate ester 75 as a yellow solid(7.9 mg, 0.0261 mmol, 64%).

Example 16 Total Synthesis of All-trans-Retinal Using IterativeSuzuki-Miyaura Reactions First Coupling—Synthesis of tetraenylboronateester (84)

A solution of the catalyst was prepared as follows: To a 4 mL vialequipped with a stir bar and containing2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1-biphenyl (4 d) (23.1 mg,0.056 mmol, 2.0 eq.) was added a solution of Pd(OAc)₂ in toluene (0.038M, 0.740 mL, 0.028 mmol, 1.0 eq.). The vial was sealed with a PTFE-linedcap and maintained at 65° C. with stirring for 15 min.

This catalyst solution was then utilized in the following procedure: Toa 40 mL I-Chem vial equipped with a magnetic stir bar and containing asolution of 83 in toluene (estimated 0.17 M, 11.5 mL, 1.96 mmol, 1.5eq.) was added anhydrous K₃PO₄ as a finely ground powder (0.833 g, 3.92mmol, 3.0 eq.), 54 a (0.342 g, 1.30 mmol, 1.0 eq.), and the catalystsolution (0.688 mL, 0.026 mmol Pd, 2 mol % Pd). The resulting mixturewas sealed with a PTFE-lined cap and stirred at 23° C. for 60 h. Themixture was then filtered through a pad of silica gel with copiousamounts of acetonitrile. To the resulting solution was added Florisil®and the solvent was removed in vacuo. The resulting powder wasdry-loaded on top of a silica gel column and flash chromatography wasperformed (hexanes:EtOAc 1:1 EtOAc EtOAC:MeCN 9:1) to yield protectedtetraenylboronate ester 84 as a yellow powder (0.377 g, 1.02 mmol, 78%).

Second Coupling—Synthesis of all-trans-retinal (49)

MIDA boronate 84 was converted to its corresponding boronic acid via thefollowing procedure: In a 7 mL Wheaton vial, to a stirred solution of 84(35.9 mg, 0.101 mmol, 1.0 eq.) in THF (1.44 mL) at 23° C. was added 1 Maq. NaOH (0.30 mL, 0.30 mmol, 3.0 eq.) and the resulting mixture wasstirred for 15 min. The reaction was then quenched with the addition of0.5 M pH 7 phosphate buffer (1.5 mL) and diluted with Et₂O (1.5 mL). Thelayers were separated and the aqueous layer was extracted with THF:Et₂O1:1 (3×3 mL). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo until a small amount of THF (˜1 mL) remained,yielding a solution of the boronic acid; TLC: (EtOAc) R_(f)=0.70,visualized by KMnO₄.

A solution of the palladium catalyst was prepared as follows: To a 1.5mL vial equipped with a magnetic stir bar and containing2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4 d) (3.6 Mg,0.0088 mmol, 2.0 eq.) was added a solution of Pd(OAc)₂ in toluene (0.038M, 0.115 mL, 0.0044 mmol, 1.0 eq.). The vial was sealed with aPTFE-lined cap and maintained at 65° C. with stirring for 15 min.

This catalyst solution was then utilized in the following procedure: Toa 4 mL vial equipped with a magnetic stir bar and containing enal 85 (10mg, 0.067 mmol, 1.0 eq.) was added the boronic acid (corresponding toboronate 84; see above) as a solution in THF (estimated 0.101 M, 1 mL,0.101 mmol, 1.5 eq.), anhydrous K₃PO₄ as a finely ground powder (42.6mg, 0.201 mmol, 3.0 eq.), and the catalyst stock solution describedabove (0.035 mL, 0.0013 mmol Pd, 2 mol % Pd). The resulting mixture wassealed with a PTFE-lined cap and stirred at 23° C. for 5 h. The reactionwas then quenched with the addition of saturated aqueous NaHCO₃ (2 mL).The layers were separated and the aqueous layer was extracted with Et₂O(3×5 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (hexanes:EtOAc 32:1) to yield all-trans-retinal (49) as abright yellow solid (12.6 mg, 0.044 mmol, 66%). ¹H NMR, ¹³C NMR, HRMS,and IR analysis of synthetic 49 were fully consistent with the datareported for the isolated natural product.

Example 17 Synthesis of Half Skeleton of Amphotericin B MacrolideSynthesis of BB₄

A 200 mL recovery flask was charged with diolCH₃—CH(OH)—OH(CH₃)—CH(OH)—CH(CH₃)—CH₂—O—CH₂—C₆H₅ (Paterson, 2001) (1.18g, 4.69 mmol, 1.0 eq.), Lipase PS (295 mg, 0.25 mass eq), and hexanes(115 mL) and the resulting slurry was stirred at 50° C. for 15 min.Vinyl acetate (4.33 mL, 47.0 mmol, 10.0 eq) was then added and thereaction mixture was stirred at 50° C. for 40 h. The resulting mixturewas cooled to 23° C. and filtered, and the residual enzyme was washedcopiously with Et₂O. The filtrate was then concentrated in vacuo and theresulting viscous, light yellow oil was purified by flash columnchromatography (hexanes:EtOAc 15:1→1:1) to yield monoacetateCH₃—CH(OAc)—CH(CH₃)—CH(OH)—CH(CH₃)—CH₂—O—CH₂—C₆H₅ as a pale yellow oil(1.05 g, 3.57 mmol, 76%).

To a stirred solution of this monoacetate (5.98 g, 20.31 mmol, 1.0 eq.)in CH₂Cl₂ (230 mL) at 0° C. was added 2,6-lutidine (7.84 mL, 67.35 mmol,3.3 eq.) and the resulting solution was cooled to −78° C. Triethylsilyltrifluoromethanesulfonate (7.11 mL, 31.43 mmol, 1.5 eq.) was then addeddropwise and the resulting solution was stirred at −78° C. for 1 h. Thereaction was then quenched with the addition of saturated aqueous NaHCO₃(115 mL) and allowed to warm to 23° C. The layers were separated and theaqueous layer was extracted with Et₂O (3×200 mL). The combined organicextracts were dried over MgSO₄ and concentrated in vacuo to give ayellow oil. Purification by flash chromatography (hexanes:EtOAc 7:1→1:1)provided the triethyl silyl etherCH₃—CH(OAc)—CH(CH₃)—CH(OTES)—CH(CH₃)—CH₂—OCH₂—C₆H₅ as a yellow oil (7.34g, 17.96 mmol, 88%).

To a 25 mL three-neck round-bottomed flask equipped with a magnetic stirbar was added palladium black (17.3 mg, 0.163 mmol, 0.6 eq.). Caution:palladium black is pyrophoric and should be maintained under inertatmosphere at all times. For this reaction, EtOH and EtOAc were freshlydistilled over activated 4 Å molecular sieves. To this flask was thenadded via cannula a solution of the triethyl silyl ether (see above;111.0 mg, 0.271 mmol, 1.0 eq.) in EtOH:EtOAc 2:1 (4.65 mL). The reactionflask was purged with H₂ (balloon) and stirred at 23° C. for 25 h undera positive pressure of H₂ (balloon). The resulting mixture was thenfiltered under N₂ pressure through a short column of Celite, flushingwith copious amounts of EtOH (Pd residue kept under solvent at alltimes). Purification by flash chromatography (hexanes:EtOAc 12:1→4:1)yielded primary alcohol CH₃—CH(OAc)—CH(CH₃)—CH(OTES)—CH(CH₃)—CH₂—OH as apale yellow oil (79.1 mg, 0.248 mmol, 91%).

To a stirred solution of oxalyl chloride (3.44 mL, 40.1 mmol, 5.0 eq.)in CH₂Cl₂ (20 mL) at −78° C. was added dropwise DMSO (5.70 mL, 80.2mmol, 10.0 eq.) and the resulting solution was stirred at −78° C. for 30min. To the reaction was then added via cannula a solution of theprimary alcohol (see above; 2.56 g, 8.02 mmol, 1.0 eq.) in CH₂Cl₂ (55.7mL) and the resulting solution was stirred at −78° C. for 1.5 h.Triethylamine (28 mL, 201 mmol, 25.0 eq.) was then added and theresulting mixture was allowed to warm to −15° C. over 40 min. Thereaction was then quenched with the addition of saturated aqueous NH₄Cl(50 mL). The layers were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×50 mL). The combined organic layers were washed withbrine (50 mL), dried over MgSO₄, and concentrated in vacuo to yieldaldehyde CH₃—CH(OAc)—CH(CH₃)—CH(OTES)—CH(CH₃)—CH═O as a yellow oil (2.36g, 7.46 mmol, 93%).

To a stirred slurry of CrCl₂ (0.204 g, 1.66 mmol, 18.0 eq.) in THF (2mL) at 23° C. was added a solution of this aldehyde (29.2 mg, 0.0923mmol, 1.0 eq.) and dichlomethylpinacolboronic ester (Wuts, 1982; Raheem,2004; 0.117 g, 0.554 mmol, 6.0 eq.) in THF (0.18 mL). A solution of LiI(0.149 g, 1.11 mmol, 12.0 eq.) in THF (0.3 mL) was then added and theresulting slurry was stirred at 23° C. for 7 h. The reaction was thenpoured into ice water (2 mL) and extracted with Et₂O (2×5 mL). Thecombined organic extracts were dried over MgSO₄, filtered throughCelite, and concentrated in vacuo. The crude material was purified byflash chromatography on Florisil® (hexanes:EtOAc 35:1→3:1) to providethe pinacolboronic ester shown below as a pale yellow oil (25.7 mg, 0.58mmol, 63%).

A 15 mL round-bottomed flask equipped with a stir bar was charged withthis pinacol boronic ester (126.9 mg, 0.288 mmol, 1.5 eq.). To thisflask was then added a solution of (E)-1-chloro-2-iodoethylene (62)(36.2 mg, 0.192 mmol, 1.0 eq.) and Pd(PPh₃)₄ (16.6 mg, 0.0144 mmol, 5mol %) as a solution in THF (4.5 mL) followed by 3 M aqueous NaOH (0.192mL, 0.576 mmol, 2.0 eq.). The resulting mixture was stirred at 23° C.for 17 h and then the reaction was quenched with saturated aqueous NH₄Cl(5 mL). The resulting mixture was diluted with diethyl ether (5 mL) andthe layers were separated. The aqueous layer was extracted with diethylether (3×5 mL) and the combined organic layers were dried over MgSO₄ andconcentrated in vacuo. Purification of the resulting residue by flashchromatography (hexanes:EtOAc 35:1→5:1 with 1% Et₃N (v/v) added to alleluents) provided dienylchloride BB₄ as a yellow oil (51.0 mg, 0.136mmol, 71%).

(E,E,E,E,E)-1,3,5,7,9-decapentenyl-(10-propyl)boronate ester (91)

MIDA boronate 68 (see Example 14) was converted to (E,E)-1,3-heptadienylboronic acid 90 via the following procedure: To a stirred mixture of 68(25.6 mg, 0.102 mmol, 1.0 eq.) in THF (1.0 mL) at 23° C. was added 1NNaOH (aq.) (0.306 mL, 0.306 mmol, 3.0 eq.) via syringe. The reactionmixture was stirred at 23° C. for 15 min. The resulting mixture wastreated with 1.0 N phosphate buffer solution (pH 7, 0.5 mL) and dilutedwith Et₂O (1.0 mL). The organic layer was separated and aqueous layerwas extracted with THF:Et₂O 1:1 (3×1.50 mL). The combined organic layerswere dried over anhydrous magnesium sulfate. After filtration, theresulting colorless solution was concentrated to ˜0.50 mL volume of THFin vacuo. THF (5.0 mL) was added and concentrated again to ˜0.25 mLvolume of THF in vacuo. The isolated yield of boronic acid 90 wasassumed to be 90% based on 68, and a 0.1836 N solution of boronic acid90 in THF (0.0918 mmol/0.50 mL of THF) was prepared using a 1.0 mL (v/v)volumetric vial. This solution was immediately used in the next reactionwithout further purification. TLC (EtOAc) R_(f)=0.88, visualized by UVlamp (λ=254 nm) or with KMnO₄.

A solution of the catalyst was prepared as follows: A 20 mL Wheaton vialequipped with a magnetic stir bar was charged with Pd(OAc)₂ (5.60 mg,0.025 mmol, 1.0 eq.) and2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4 c)(24.5 mg, 0.050 mmol, 2.0 eq.). Toluene (3.0 mL) was added and the vialwas sealed with a PTFE-lined plastic cap. The resulting mixture wasstirred at 23° C. for 1 h to yield a reddish Pd/4 c catalystsolution'(0.00833 N Pd in toluene).

This catalyst solution was then utilized in the following procedure: A10 mL Wheaton vial equipped with a magnetic stir bar was charged withBB₃ (16.5 mg, 0.0612 mmol, 1.0 eq.), Cs₂CO₃ (40.0 mg, 0.1224 mmol, 2.0eq.), the 0.1836 N boronic acid in THF solution (0.0918 mmol, 0.50 mL),and the catalyst solution (0.110 mL, 1.5 mol % Pd). Toluene (1.64 mL)was then added and the vial was sealed with a PTFE-lined plastic cap andstirred for 18 h at 45° C. The resulting deep orange mixture was dilutedwith EtOAc (5.0 mL) and filtered through a short pad of Florisil®. Thefiltrate was concentrated in vacuo to provide an orange solid. The crudeproduct was purified by flash chromatography on Florisil® (petroleumether:EtOAc 1:1→EtOAc→EtOAc:MeCN 9:1) to give 91 as a light yellow solid(8.40 mg, 0.0255 mmol, 42%).

½ Of the Amphotericin B Macrolide (92)

A solution of the catalyst was prepared as follows: An oven-driedWheaton vial equipped with a magnetic stir bar was charged with Pd(OAc)₂(5.60 mg, 0.025 mmol, 1.0 eq.) and2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4 c)(24.5 mg, 0.050 mmol, 2.0 eq.). Toluene (3.0 mL) was added and the vialwas sealed with a PTFE-lined plastic cap. The resulting mixture wasstirred at 23° C. for 1 h to yield a reddish Pd/4 c catalyst solution(0.00833 N Pd in toluene).

This catalyst solution was then utilized in the following procedure: Anoven-dried Wheaton vial equipped with a magnetic stir bar was chargedwith BB₄ (7.0 mg, 0.0187 mmol, 1.0 eq.), 91 (14.0 mg, 0.0421 mmol, 2.25eq.), the catalyst solution (0.034 mL, 1.5 mol % Pd), and THF (1.50 mL),and the vial was sealed with a PTFE-lined plastic cap. Degassed 1N NaOH(aq.) (0.211 mL, 0.211 mmol, 5.00 eq. based on 91) was added into thevial via syringe. The yellow reaction mixture was stirred for 15 min 23°C. and then stirred at 45° C. for 16 hr. The resulting heterogeneousdeep reddish mixture was diluted with ethyl acetate (5.0 mL) and driedover anhydrous magnesium sulfate. The orange solution was filteredthrough short pad Florisil® and the filtrate was concentrated in vacuoto provide an orange solid. The crude product was purified by flashchromatography on Florisil® (petroleum ether:EtOAc 60:1) to give 92 as ayellow solid (4.60 mg, 0.0090 mmol, 48%).

Example 18 Synthesis of β-Parinaric Acid (E)-1-Butenylboronic acid (23)

A 150 mL bomb flask equipped with a magnetic stir bar was charged withBH₃.SMe₂ (1.8 mL, 19.4 mmol, 1.0 eq.) and THF (11 mL). The solution wascooled to 0° C. and (+)-α-pinene (6.3 mL, 39.7 mmol, 2.0 eq.) was addeddropwise. The solution was stirred at 0° C. for 10 min then allowed towarm to 23° C. and stirred at 23° C. for 2 h, during which time a whiteprecipitate formed. The solution was then recooled to 0° C. and anexcess of 1-butyne was condensed into the reaction via a balloonresulting in a clear, colorless solution. The flask was then sealed witha Teflon screw cap and was stirred at 0° C. for 30 min, warmed to 23°C., and stirred at 23° C. for 1.5 h. The solution was recooled to 0° C.and acetaldehyde (10.4 mL, 185 mmol, 9.5 eq.) was added. The bomb flaskwas resealed with the Teflon screw cap and the reaction was stirred at40° C. for 14 h. The reaction was allowed to cool to 23° C. and water (5mL) was added. After stirring for 3 h at 23° C., the solution wasdiluted with EtOAc (50 mL), dried over MgSO₄, and concentrated in vacuo.The resulting residue was taken up in hexanes (50 mL) and the resultingmixture was extracted with 10% aqueous NaOH (2×10 mL). The combinedaqueous extractions were washed with hexanes (2×20 mL) and thenacidified to pH 2-3 with concentrated hydrochloric acid. The acidifiedaqueous layer was then extracted with EtOAc (3×30 mL), and the combinedorganic extracts were washed with saturated aq. NaHCO₃ (50 mL), driedover MgSO₄, and concentrated in vacuo to yield the title compound 93 asa colorless solid (0.928 g, 9.3 mmol, 48%).

(E,E,E)-1,3,5-Octatrienylboronate ester (94)

A solution of the palladium catalyst was prepared as follows: To a 4 mLvial equipped with a magnetic stir bar and containing2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4 c)(17.3 mg, 0.036 mmol, 2.0 eq.) was added a solution of Pd(OAc)₂ in THF(0.0109 M, 1.664 mL, 0.018 mmol, 1.0 eq.). The vial was sealed with aPTFE-lined cap and stirred at 23° C. for 30 min.

This catalyst solution was then utilized in the following procedure: Toa 20 mL I-Chem vial equipped with a stir bar and containing(E)-1-butenylboronic acid (93) (113 mg, 1.13 mmol, 2.0 eq.) was added 54b (138 mg, 0.521 mmol, 1.0 eq.), anhydrous K₃PO₄ as a finely groundpowder (301 mg, 1.42 mmol, 2.5 eq.), THF (7.9 mL), and the catalystsolution (0.780 mL, 0.0085 mmol Pd, 1.5 mol % Pd). The resulting mixturewas sealed with a PTFE-lined cap and stirred at 45° C. for 23 h. (54 band product 94 were best separated on TLC plates by eluting three timeswith hexanes:EtOAc 2:3). The mixture was then filtered through a pad ofsilica gel with copious amounts of acetonitrile. To the resultingsolution was added Florisil® gel and then the solvent was removed invacuo. The resulting powder was dry-loaded on top of a silica gel columnand flash chromatography was performed (Et₂O→Et₂O:MeCN 4:1) to yield 94as a yellow powder (120 mg, 0.456 mmol, 88%).

10-iodo-9-decenoic acid (95)

To a suspension of CrCl₂ (454 mg, 3.75 mmol, 7.0 eq.) in THF (1.5 mL) at23° C. was added dropwise a solution of (E)-methyl 10-iododec-9-enoate(100 mg, 0.537 mmol, 1.0 eq.) and iodoform (422 mg, 1.07 mmol, 2.0 eq.)in dioxane (9.2 mL). After stirring for 12 h, the reaction mixture wasdiluted with Et₂O (10 mL) and poured into water (10 mL). The layers wereseparated and the aqueous layer was extracted with Et₂O (3×15 mL). Thecombined organic extracts were washed with brine (10 mL), dried overMgSO₄, and concentrated in vacuo. Purification of the crude product byflash chromatography (hexanes→hexanes:EtOAc 9:1) provided10-iodo-9-decenoate methyl ester as a yellow oil (105 mg, 0.337 mmol,63%). ¹H NMR indicated an E:Z ratio of 10:1.

To a stirred solution of this 10-iodo-9-decenoate methyl ester (51.0 mg,0.164 mmol, 1.0 eq.) in THF:H₂O 3:1 (3.3 mL) was added LiOH (69.0 mg,1.64 mmol, 10.0 eq.). The reaction was stirred at 50° C. for 4 h beforediluting with Et₂O (5 mL) and pouring into 1 M aqueous HCl (5 mL). Thelayers were separated and the aqueous layer was extracted with Et₂O (3×5mL). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄, and concentrated in vacuo. Purification of the crudeproduct by flash chromatography (hexanes:EtOAc 5:1 EtOAc) provided 95 asa pale yellow solid (44.0 mg, 0.149 mmol, 91%). ¹H NMR indicated an E:Zratio of 10:1.

β-Parinaric Acid (96)

MIDA boronate 94 was converted to its corresponding boronic acid via thefollowing procedure: To a stirred solution of 94 (24.7 mg, 0.094 mmol,1.0 eq.) in THF (1.34 mL) at 23° C. was added 1 M aq. NaOH (0.28 mL,0.28 mmol, 3.0 eq.) and the resulting mixture was stirred at 23° C. for15 min. The reaction was then quenched with the addition of 0.5 M pH 7phosphate buffer (1.5 mL) and diluted with Et₂O (1.5 mL). The layerswere separated and the aqueous layer was extracted with THF:Et₂O 1:1(3×3 mL). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo until a small amount of THF (˜3.7 mL) remained,yielding a solution of the boronic acid; TLC (EtOAc): R_(f)=0.63,visualized with KMnO₄.

A solution of the palladium catalyst was prepared as follows: To a 4 mLvial equipped with a magnetic stir bar and containing2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1-biphenyl ligand (4c) (2.1 mg, 0.0044 mmol, 2.0 eq.) was added a solution of Pd(OAc)₂ inTHF (0.004 M, 0.545 mL, 0.0022 mmol, 1.0 eq.). The vial was sealed witha PTFE-lined cap and stirred at 23° C. for 30 min.

This catalyst solution was then utilized in the following procedure: Toa 20-mL I-Chem vial equipped with a magnetic stir bar and containing 95(18.5 mg, 0.062 mmol, 1.0 eq.; E:Z 7:1 by ¹H NMR) was added the boronicacid corresponding to boronate 94 (see above; 3.7 mL, estimated 0.094mmol, 1.5 eq.) and the catalyst solution described above (0.31 mL,0.0013 mmol Pd, 2 mol % Pd). The resulting mixture was sealed with ateflon-lined septum cap and 1 M aqueous NaOH (0.19 mL, 0.190 mmol, 3.0eq.) was added. The reaction was stirred at 23° C. for 40 min and wasthen quenched with the addition of saturated aqueous NH₄Cl (3 mL). Thelayers were separated and the aqueous layer was extracted with Et₂O (3×5mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo. The resulting crude product was purified by flashchromatography (hexanes:Et₂O 4:1→Et₂O) to yield β-parinaric acid 96 as afluorescent solid (14.8 mg, 0.054 mmol, 86%). ¹H NMR indicated a 7:1mixture of β-parinaric acid:9-(Z) parinaric acid (arising from 7:1 E:Zmixture of starting material 95). ¹H NMR and ¹³C NMR analysis ofsynthetic 96 were fully consistent with the data previously reported for(β-parinaric acid.

Example 19 In Situ Cross-Coupling of Protected Organoboronic Acids withan Aryl Halide Reaction of β-methoxyphenyl MIDA-boronate (300)

To a 50 mL round-bottom flask equipped with a stir bar was added3-methoxyphenylboronic acid (6.591 mmol, 1.002 g) andN-methyliminodiacetic acid (6.27 mmol, 922 mg). To the flask was addedtoluene (6 mL) and DMSO (2 mL). The flask was fitted with a Dean-Starktrap filled with toluene. The mixture was refluxed for 2.5 h. Thesolution was concentrated in vacuo (1 Torr, 90-100° C.). The resultingviscous yellow oil was frozen at −78° C., then was placed on alypholizer for 12 h. The nearly solid yellow oil was suspended inacetone (3 mL). To the mixture was added Et₂O (6 mL). The mixture wasgently agitated. The yellow solution was decanted away from theoff-white solid. The solid was placed under vacuum (1 Torr) with heating(app. 80° C.) for 30 min. to afford the desired product as afree-flowing, off-white solid, 1.562 g (95%).

To a 20 mL vial equipped with a teflon-coated stirbar was added4-bromoacetophenone (0.200 g, 1.005 mmol), 3-methoxyphenyl MIDA-boronate(0.397 g, 1.509 mmol), and sodium hydroxide (0.302 g, 7.550 mmol). Thevial was promptly brought into a glove box, and to it was addedtetrakis(triphenylphosphine)-palladium(0) (0.023 g, 0.020 mmol) and THF(10 mL). The vial was sealed with a septum cap and taken out of theglove box. H2O (2 mL), degassed for 20 min by sparging with argon, wasadded to the vial by syringe. The reaction was maintained at 60° C. withvigorous stirring for 24 h. After cooling to room temperature, thereaction was poured into 10 mL 1M aqueous NaOH. The aqueous layer wasseparated and extracted with ether 3×10 mL. The combined organicfractions were washed with 10 mL saturated aqueous NaHCO3 and 10 mLbrine and dried over MgSO4. Solvent was removed in vacuo (˜20 Torr and30° C.) to afford the crude product as a yellow oil. The crude productwas purified by column chromatography (50:45:5 hexane/CH2Cl2/EtOAc) toyield a clear colorless liquid which crystallized under vacuum (0.220 g,97%). This reaction may be run at a total concentration of 0.33 M (2 mLTHF, 1 mL H2O) in 96% yield. The concentrated reaction was run in thesame size vial. Very efficient stirring may be important, as somecomponents of the reaction are not entirely soluble during the entirecourse of the reaction.

Reaction of 4-pyridyl MIDA-boronate (302)

To a 50 mL round-bottom flask equipped with a stir bar was added4-pyridylboronic acid (8.160 mmol, 1.002 g; purple solid as receivedfrom Frontier Scientific) and N-methyliminodiacetic acid (7.728 mmol,1.136 g). To the flask was added toluene (6 mL) and DMSO (8 mL). Theflask was fitted with a Dean-Stark trap filled with toluene. The mixturewas refluxed for 2 h. As the reaction progressed, a dark solidaccumulated on the sides of the flask. This material was not soluble inacetone and dissolved in water to form a blue/purple solution. Thismaterial was ascribed to the impurity of the starting material. Themixture was filtered through a thin pad of Celite. The Celite pad waswashed with acetone (2×10 mL). The solution was concentrated in vacuo (1Torr, 90-100° C.). The dark purple residue was suspended in MeCN (5 mL).The mixture was agitated. To the mixture was added Et₂O (10 mL). Themixture was agitated and the purple solution was then decanted away fromthe purple solid. The solid was washed with Et2O (5 mL). Residualsolvent was removed in vacuo to afford the desired product asfree-flowing, purple solid, 1.341 g (74%). This material wascontaminated with DMSO (estimated 5%), which was removed viatrituration, in which the solid material was suspended in MeCN (5 mL),and the suspension was rotated on a rotary evaporator at 40° C. for 5min. to facilitate mixing. To the mixture was added Et₂O (10 mL), andthe mixture was agitated. The solution was decanted away from the purplesolid. Residual solvent was removed in vacuo to afford the desiredproduct as free-flowing, purple solid, 1.235 g (68%).

To a 20 mL vial equipped with a teflon-coated stirbar was added4-bromoacetophenone (0.200 g, 1.005 mmol), 4-pyridyl MIDA-boronate(0.353 g, 1.508 mmol), and K2CO3 (1.043 g, 7.55 mmol). The vial waspromptly brought into a glove box, and to it was addedtetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol) anddioxane (10 mL). The vial was sealed with a septum cap and taken out ofthe glove box. H2O (2 mL), degassed for 20 min by sparging with argon,was added to the vial by syringe. The reaction was maintained at 100° C.with vigorous stirring for 12 h. After cooling to room temperature, thereaction was poured into 10 mL ether and 10 mL 1M NaOH(aq). The aqueouslayer was separated and extracted with ether 3×10 mL. The combinedorganic fractions were washed with 10 mL sat'd NaHCO3(aq) and 10 mLbrine and dried over MgSO4. Solvent was removed in vacuo (˜20 Torr and30° C.) to afford the crude product as a yellow solid. The crude productwas purified by column chromatography (100% EtOAc) to yield a colorlesscrystalline solid (0.188 g, 95%). This reaction can be run at a totalconcentration of 0.33 M (2 mL dioxane, 1 mL H2O) in 96% yield. Theconcentrated reaction was run in the same size vial. Very efficientstirring may be important, as some components of reaction are notentirely soluble during the entire course of the reaction.

Example 20 Preparation of Protected Organoboronic Acids without theFormation of the Corresponding Free Boronic Acid Phenyl-MIDA-Boronate(304)

To a dry 100 mL Schlenk flask equipped with a stir bar, fitted with arubber septum, and placed under Ar atmosphere, was added THF (25 mL),bromoboenzene (2.0 mL, 19 mmol) and triisopropyl borate (5.3 mL, 23mmol). The stirred solution was cooled to −78° C. To the solution wasadded n-BuLi (9.1 mL, 2.5 M, 23 mmol). The pale orange solution wasstirred for 15 min. The solution was allowed to warm to room temperaturewith stirring for 30 min. To the solution was added DMSO (15 mL) andN-methyliminodiacetic acid (8.39 g, 57.1 mmol). The flask was fittedwith a distillation apparatus. The mixture was brought to reflux, and assolvent was distilled the distillation pot was periodically charged withtoluene to maintain a constant volume. The crude reaction mixture wasconcentrated in vacuo to afford an off-white solid. To the flask wasadded acetone (200 mL). The resulting suspension was filtered through athin pad of celite. The filtrate was concentrated in vacuo. Theresulting residue was adsorbed onto Florisil gel. This powder wasdry-loaded onto a silica gel column slurry packed in Et₂O. The columnwas flushed with Et₂O (approximately 400 mL), then was eluted withEt₂O:MeCN (5:1) to afford 304 as a colorless solid, 3.592 g (81%).

Vinyl-MIDA-Boronate (306)

To a dry 6 mL vial fitted with a septum cap, equipped with a stir bar,and placed under Ar atmosphere was added BBr₃ in CH₂Cl₂ (1.3 mL, 1.0 M,1.3 mmol). To the stirred solution was added vinyltrimethylsilane (140μL, 0.983 mmol). The solution was stirred at room temperature for 13 h.Separately, a dry 25 mL round bottom flask equipped with a stir bar,fitted with a rubber septum, and placed under Ar atm. was charged withsodium N-methyliminodiacetate (478 mg, 2.50 mmol) and DMSO (4 mL). Tothis stirred suspension was added dropwise by syringe the crudevinylboron dibromide solution. The mixture was stirred for 5 min. Themixture was concentrated in vacuo. The residue was adsorbed ontoFlorisil gel from an acetone suspension. The resulting powder wasdry-loaded onto a silica gel column slurry packed in Et₂O. The columnwas flushed with Et₂O (app. 200 mL), then was eluted with Et₂O:MeCN(3:1) to afford 306 as a colorless solid, 88 mg (48%).

Example 21 Three-Component Coupling in a Single Reaction Mixture

FIG. 24 shows structures and reaction schemes for a cross-couplingreaction of three separate components, carried out in a single reactionmixture. To a flame-dried 7-mL vial was added4-bromophenyl-MIDA-boronate (8 a, 0.0625 g, 0.200 mmol, 1.00 eq) andp-tolylboronic acid (0.0410 g, 0.3016, 1.50 eq). The vial was capped w/aKimwipe® and brought immediately into a glovebox, whereupon finelyground potassium phosphate (0.2975 g, 1.40 mmol, 7.00 eq) andtetrakis(triphenylphosphine) palladium(II) (0.0116 g, 0.0100 mmol, 0.05eq) were added. A magnetic stirbar and dioxane (2.0 mL) were added, andthe vial was sealed with a PTFE-lined screwcap. Out of the glovebox, thereaction was maintained with stirring at 100° C. for 12 h. The vial wasallowed to cool to 23° C., and again brought into a glovebox, whereupona 20 μL aliqout was taken for ¹H-NMR analysis. 4-bromoacetophenone(0.0797 g, 0.400 mmol, 2.0 eq) was added as a solution in dioxane (1.0mL). The vial was sealed with a PTFE-lined septum screwcap. Out of theglovebox, water (0.60 mL) was added to the vial by syringe. The reactionwas maintained with stirring at 100° C. for an additional 12 h.

After cooling to 23° C., the reaction, which consisted of a whitesuspension in the upper organic phase and a clear colorless loweraqueous phase, was poured into a mixture of 1 M aqueous NaOH (10 mL) andEt₂O (10 mL). The organic phase phase, which included an insoluble whiteprecipitate, was isolated, and the aqueous phase was extracted with Et₂O(3×10 mL). The combined organic fractions were washed with sat'd aq.NaHCO₃ (1×10 mL) and brine (1×10 mL). The white precipitate was removedby filtration, and the remaining solution was concentrated in vacuo.Analysis by ¹H NMR revealed the resulting white residue to be a 1:1mixture of products 308 and 310. Analysis by ¹H NMR revealed theisolated white precipitate to be exclusively the desired compound 308.¹H NMR analysis of the aliquot taken at 12 h indicated completeconversion of 8 a.

While various embodiments of the invention have been described, it willbe apparent to those of ordinary skill in the art that other embodimentsand implementations are possible within the scope of the invention.Accordingly, the invention is not to be restricted except in light ofthe attached claims and their equivalents.

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What is claimed is:
 1. A protected organoboronic acid, comprising: aboron having an sp³ hybridization, a conformationally rigid trivalentprotecting group bonded to the boron, and an organic group bonded to theboron through a boron-carbon bond; where the organic group is notselected from the group consisting of —C₂H₅, —C(CH₃)₂CH(CH₃)₂,cyclopentyl, tetrahydropyranyl, norbornyl,2,4,4-trimethyl-bicyclo[3.1.1]heptanyl, —C₆H₅, —C₆H₄—CH₃, —C₆H₄—CHO,—C₆H₄—OCH₃, —C₆H₄—F, —C₆H₄—Br, —C₆H₄—CF₃, and —C₆H₄—NO₂.
 2. Theprotected organoboronic acid of claim 1, where the organic group furtheris not selected from the group consisting of —C₆H₄—C₆H₄—CH₃,-4-bromothiophenyl, -4-tolyl-thiophenyl, -cyclopropyl-C₆H₄—Br,-cyclopropyl-C₆H₄—C₆H₄—CH₃, —CH═CH—C₆H₄—Br, —CH═CH—C₆H₄—C₆H₄—CH₃,-5-bromo-2-benzofuranyl, -5-(1-propenyl)-2-benzofuranyl,-2-methoxymethoxy-4-methoxy-5-bromophenyl, and-2-methoxymethoxy-4-methoxy-5-(5-(1-propenyl)-2-benzofuranyl)phenyl. 3.The protected organoboronic acid of claim 1, where the protectedorganoboronic acid is represented by formula (II):R¹—B-T  (II); where R¹ represents the organic group, and comprises atleast one group selected from the group consisting of an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, and a heteroaryl group, Trepresents the conformationally rigid trivalent protecting group, and Brepresents the boron having sp³ hybridization.
 4. The protectedorganoboronic acid of claim 3, where R¹ comprises a functional group. 5.The protected organoboronic acid of claim 4, where the functional groupis selected from the group consisting of halogen, pseudohalogen,alcohol, aldehyde, ketone, carboxylic acid, thiol, sulfone, sulfoxide,amine, phosphine, phosphite, phosphate, metal-containing groups, aprotected alcohol, a protected carboxylic acid, and a protected amine.6. The protected organoboronic acid of claim 3, where R¹ comprises atleast two alternating carbon-carbon double bonds.
 7. The protectedorganoboronic acid of claim 3, where R¹ is a group represented byformula (III):Y—R²—(R³)_(m)—  (Ill); where Y represents a halogen group or apseudohalogen group, R² represents an aryl group, R³ comprises at leastone group selected from the group consisting of an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, and a heteroaryl group, andm is 0 or
 1. 8. The protected organoboronic acid of claim 3, where theprotected organoboronic acid is represented by formula (IV):R⁴—(R⁵)_(m)—B-T  (IV); where R⁴ and R⁵ together represent the organicgroup, and independently comprise at least one group selected from thegroup consisting of an alkyl group, a heteroalkyl group, an alkenylgroup, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group,an aryl group, and a heteroaryl group, m is 0 or 1, T represents theconformationally rigid trivalent protecting group, and B represents theboron having sp³ hybridization.
 9. The protected organoboronic acid ofclaim 8, where R⁴ is not an aryl group comprising a halogen substituentgroup or a pseudohalogen substituent group.
 10. The protectedorganoboronic acid of claim 9, where R⁴ is comprises at least one groupselected from the group consisting of an alkyl group, a heteroalkylgroup, an alkenyl group, a heteroalkenyl group, an alkynyl group, and aheteroalkynyl group, and R⁴ further comprises a halogen substituentgroup or a pseudohalogen substituent group.
 11. The protectedorganoboronic acid of claim 9, where R⁴ does not contain a halogen groupor pseudohalogen group.
 12. The protected organoboronic acid of claim11, where R⁴ comprises at least one group selected from the groupconsisting of an aryl group, and a heteroaryl group.
 13. A method ofperforming a chemical reaction, comprising: contacting a protectedorganoboronic acid with a reagent, the protected organoboronic acidcomprising a boron having an sp³ hybridization, a conformationally rigidtrivalent protecting group bonded to the boron, and an organic groupbonded to the boron through a boron-carbon bond; where the organic groupis chemically transformed, and the boron is not chemically transformed.14. The method of claim 13, further comprising removing theconformationally rigid trivalent protecting group from the boron. 15.The method of claim 13, where the protected organoboronic acid isrepresented by formula (II):R¹—B-T  (II); where R¹ represents the organic group, and comprises atleast one group selected from the group consisting of an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, and a heteroaryl group, Trepresents the conformationally rigid trivalent protecting group, and Brepresents the boron having sp³ hybridization.
 16. The method of claim15, where R¹ is a group represented by formula (III):Y—R²—(R³)_(m)—  (Ill), where Y represents a halogen group or apseudohalogen group; R² represents an aryl group; R³ comprises at leastone group selected from the group consisting of an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, and a heteroaryl group; andm is 0 or
 1. 17. The method of claim 15, further comprising forming thecompound represented by formula (II) by reacting a compound representedby formula (I):F¹—B(OH)₂  (I); with a protecting reagent.
 18. The method of claim 13,where the organic group comprises at least two alternating carbon-carbondouble bonds.
 19. The method of claim 13, where the protectedorganoboronic acid is selected from the group consisting of: protectedorganoboronic acids 3 a, 3 c, 8 a, 8 b, 8 c, 8 d, 8 e, 8 f, 8 e, 9 a, 9b, 9 c, 9 d, 9 e, 9 f, 13, 14, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26,27, 30, 54 a, 54 b, 54 c, 54 d, 61, 64, 66, 68, 70, 72, 74, 75, 80, 84,91, 94, 300, 302, 304, and
 306. 20. The method of claim 13, where theprotected organoboronic acid is the protected organoboronic acid ofclaim
 2. 21. The method of claim 13, where the chemical reaction isselected from the group consisting of a Suzuki-Miyaura reaction, anoxidation, a reduction, an Evans' aldol reaction, an HWE olefination, aTakai olefination, an alcohol silylation, a desilylation, ap-methoxybenzylation, an iodination, a Negishi cross-coupling, a Heckcoupling, a Miyaura borylation, a Stille coupling, and a Sonogashiracoupling.
 22. The method of claim 13, where the chemical reaction is anoxidation reaction selected from a Swern oxidation and a “Jonesreagents” oxidation.
 23. A method of performing a chemical reaction,comprising: contacting a protected organoboronic acid and anorganohalide with a palladium catalyst, in the presence of aqueous base;the protected organoboronic acid comprising a boron having an sp³hybridization, a conformationally rigid trivalent protecting groupbonded to the boron, and an organic group bonded to the boron through aboron-carbon bond; to provide a cross-coupled product.
 24. The method ofclaim 23, where the protected organoboronic acid is represented byformula (II):R¹—B-T  (II); where R¹ represents the organic group, and comprises atleast one group selected from the group consisting of an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, and a heteroaryl group, Trepresents the conformationally rigid trivalent protecting group, and Brepresents the boron having sp³ hybridization.
 25. The method of claim24, where R¹ is a group represented by formula (III):Y—R²—(R³)_(m)—  (III), where Y represents a halogen group or apseudohalogen group; R² represents an aryl group; R³ comprises at leastone group selected from the group consisting of an alkyl group, aheteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, and a heteroaryl group; andm is 0 or
 1. 26. The method of claim 24, further comprising forming thecompound represented by formula (II) by reacting a compound representedby formula (I):R¹—B(OH)₂  (I); with a protecting reagent.
 27. The method of claim 23,further comprising forming the compound represented by formula (XI) byreacting a compound represented by formula (XII):

with N-methyliminodiacetic acid.
 28. The method of claim 23, where theorganic group comprises at least two alternating carbon-carbon doublebonds.
 29. The method of claim 23, where the protected organoboronicacid is selected from the group consisting of: protected organoboronicacids 3 a, 3 c, 8 a, 8 b, 8 c, 8 d, 8 e, 8 f, 8 e, 9 a, 9 b, 9 c, 9 d, 9e, 9 f, 13, 14, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 30, 54 a, 54b, 54 c, 54 d, 61, 64, 66, 68, 70, 72, 74, 75, 80, 84, 91, 94, 300, 302,304, and
 306. 30. The method of claim 23, where the protectedorganoboronic acid is the protected organoboronic acid of claim
 2. 31. Amethod of forming the protected organoboronic acid of claim 3,comprising: reacting a compound represented by formula (I):R¹—B(OH)₂  (I); with a protecting reagent.
 32. The method of claim 31,where the compound represented by formula (I) is formed in situ.
 33. Amethod of forming the protected organoboronic acid of claim 8,comprising: reacting a compound represented by formula (V):R⁴—(R⁵)_(m)—B(OH)₂  (V); with a protecting reagent.
 34. The method ofclaim 33, where the compound represented by formula (V) is formed insitu.